8-azabicyclo[3.2.1]octyl-2-hydroxybenzamide compounds as mu opioid receptor antagonists

ABSTRACT

The invention provides 8-azabicyclo[3.2.1]octyl-2-hydroxybenzamide compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R 2 , R 7 , and m are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are antagonists at the mu opioid receptor. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat conditions associated with mu opioid receptor activity, and processes and intermediates useful for preparing such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Nos.60/966,364, filed on Aug. 27, 2007, and 61/051,065, filed on May 7,2008, the disclosures of which are incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is directed to 8-azabicyclo[3.2.1]octane compounds whichare useful as mu opioid receptor antagonists. The invention is alsodirected to pharmaceutical compositions comprising such compounds,methods of using such compounds for treating or ameliorating medicalconditions mediated by mu opioid receptor activity, and processes andintermediates useful for preparing such compounds.

2. State of the Art

It is now generally understood that endogenous opioids play a complexrole in gastrointestinal physiology. Opioid receptors are expressedthroughout the body, both in the central nervous system and inperipheral regions including the gastrointestinal (GI) tract.

Compounds which function as agonists at opioid receptors, of whichmorphine is a prototypical example, are the mainstays of analgesictherapy for the treatment of moderate to severe pain. Unfortunately, useof opioid analgesics is often associated with adverse effects on the GItract, collectively termed opioid-induced bowel dysfunction (OBD). OBDincludes symptoms such as constipation, decreased gastric emptying,abdominal pain and discomfort, bloating, nausea, and gastroesophagealreflux. Both central and peripheral opioid receptors are likely involvedin the slowdown of gastrointestinal transit after opioid use. However,evidence suggests that peripheral opioid receptors in the GI tract areprimarily responsible for the adverse effects of opioids on GI function.

Since the side effects of opioids are predominantly mediated byperipheral receptors, whereas the analgesia is central in origin, aperipherally selective antagonist can potentially block undesirableGI-related side effects without interfering with the beneficial centraleffects of analgesia or precipitating central nervous system withdrawalsymptoms.

Of the three major opioid receptor subtypes, denoted mu, delta, andkappa, most clinically-used opioid analgesics are thought to act via muopioid receptor activation to exert analgesia and to alter GI motility.Accordingly, peripherally selective mu opioid antagonists are expectedto be useful for treating opioid-induced bowel dysfunction. Preferredagents will demonstrate significant binding to mu opioid receptors invitro and be active in vivo in GI animal models.

Postoperative ileus (POI) is a disorder of reduced motility of the GItract that occurs after abdominal or other surgery. The symptoms of POIare similar to those of OBD. Furthermore, since surgical patients areoften treated during and after surgery with opioid analgesics, theduration of POI may be compounded by the reduced GI motility associatedwith opioid use. Mu opioid antagonists useful for treating OBD aretherefore also expected to be beneficial in the treatment of POI.

SUMMARY OF THE INVENTION

The invention provides novel compounds that possess mu opioid receptorantagonist activity.

Accordingly, the invention provides a compound of formula (I):

wherein:

R⁷ is hydrogen or —CH₂—R¹;

R¹ is C₄₋₁₀ alkyl, C₃₋₁₂cycloalkyl, or phenyl, wherein C₃₋₁₂cycloalkyland phenyl are each optionally substituted with one or two halo;

R² is selected from —C(O)R³, —C(O)NHR⁴, —C(O)OR⁵, —S(O)₂R⁶, and —C(O)R⁸;

R³ is C₁₋₆ alkyl substituted with one or two substituents selected from—OR^(a), —S(O)₂R^(b), and —C(O)R^(c);

R⁴ and R⁵ are each independently C₁₋₆ alkyl substituted with one or twosubstituents selected from —OR^(a) and —S(O)₂R^(b);

R⁶ is C₁₋₃alkyl;

R⁸ is phenyl, optionally substituted with one or two halo;

R^(a) is hydrogen or C₁₋₃alkyl;

R^(b) is C₁₋₃alkyl;

R^(c) is selected from hydrogen, C₁₋₃alkyl, and benzyl; and

m is 1 or 2;

provided that when R⁷ is hydrogen, R² is —C(O)R⁸;

or a pharmaceutically-acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising acompound of the invention and a pharmaceutically-acceptable carrier.

The invention also provides a method of treating a disease or conditionassociated with mu opioid receptor activity, e.g. a disorder of reducedmotility of the gastrointestinal tract such as opioid-induced boweldysfunction and post-operative ileus, the method comprisingadministering to the mammal, a therapeutically effective amount of acompound or of a pharmaceutical composition of the invention.

The compounds of the invention can also be used as research tools, i.e.to study biological systems or samples, or for studying the activity ofother chemical compounds. Accordingly, in another of its method aspects,the invention provides a method of using a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as a research toolfor studying a biological system or sample or for discovering newcompounds having mu opioid receptor activity, the method comprisingcontacting a biological system or sample with a compound of theinvention and determining the effects caused by the compound on thebiological system or sample.

In separate and distinct aspects, the invention also provides syntheticprocesses and intermediates described herein, which are useful forpreparing compounds of the invention.

The invention also provides a compound of the invention as describedherein for use in medical therapy, as well as the use of a compound ofthe invention in the manufacture of a formulation or medicament fortreating a disease or condition associated with mu opioid receptoractivity, e.g. a disorder of reduced motility of the gastrointestinaltract, in a mammal.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides 8-azabicyclo[3.2.1]octane mu opioid receptorantagonists of formula (I), or pharmaceutically-acceptable salts orsolvates thereof. The following substituents and values are intended toprovide representative examples of various aspects of this invention.These representative values are intended to further define such aspectsand are not intended to exclude other values or limit the scope of theinvention.

In a specific aspect, R⁷ is hydrogen or —CH₂—R¹.

In another specific aspect, R⁷ is hydrogen.

In a specific aspect, R⁷ is —CH₂—R¹ wherein R¹ is C₄₋₁₀ alkyl,C₃₋₁₂cycloalkyl, or phenyl, wherein C₃₋₁₂cycloalkyl and phenyl are eachoptionally substituted with one or two halo.

In another specific aspect, R⁷ is —CH₂—R¹ wherein R¹ is C₄₋₆alkyl,C₃₋₆cycloalkyl, or phenyl, wherein C₃₋₆cycloalkyl and phenyl are eachoptionally substituted with one or two fluoro.

In other specific aspects, R⁷ is —CH₂—R¹ wherein R¹ is C₄₋₆alkyl orC₃₋₆cycloalkyl, wherein C₃₋₆cycloalkyl is optionally substituted withone or two fluoro. Representative R¹ groups within this aspect include,but are not limited to, 1-ethylpropyl, tert-butyl, cyclopentyl,cyclohexyl, phenyl, 4,4-difluorocyclohexyl, 4-fluorocyclohexyl,2,4-difluorophenyl, and the like. In yet another aspect, R⁷ is —CH₂—R¹wherein R¹ is 1-ethylpropyl, tert-butyl, cyclohexyl, or4,4-difluorocyclohexyl.

In a specific aspect, R² is selected from —C(O)R³, —C(O)NHR⁴, —C(O)OR⁵,—S(O)₂R⁶, and —C(O)R⁸.

In another specific aspect, R² is selected from —C(O)R³, —C(O)NHR⁴,—C(O)OR⁵, and —S(O)₂R⁶.

In another specific aspect, R² is selected from —C(O)R³, —C(O)NHR⁴, and—S(O)₂R⁶.

In a specific aspect, R² is —C(O)R³, wherein R³ is C₁₋₆ alkylsubstituted with one or two substituents selected from —OR^(a),—S(O)₂R^(b), and —C(O)R^(c).

In a specific aspect, R² is —C(O)R³ wherein R³ is C₁₋₆ alkyl substitutedwith one or two substituents selected from —OR^(a) and —S(O)₂R^(b). Inyet another specific aspect, R² is —C(O)R³, wherein R³ is C₁₋₃alkylsubstituted with one or two —OH or with one —S(O)₂CH₃. Representative R²groups within this aspect include, but are not limited to, —C(O)CH₂OH,—C(O)CH(OH)CH₂OH, and —C(O)CH₂S(O)₂CH₃. In yet another specific aspect,R² is —C(O)R³, wherein R³ is C₁₋₃alkyl substituted with —C(O)R^(c).

In still another specific aspect, R² is —C(O)R⁸ where R⁸ is phenyloptionally substituted with one or two substituents selected from fluoroand chloro.

In a specific aspect, R^(a) is hydrogen or C₁₋₃alkyl. In anotherspecific aspect, R^(a) is hydrogen or methyl. In yet another specificaspect, R^(a) is hydrogen

In a specific aspect, R^(b) is C₁₋₃alkyl. In another specific aspect,R^(b) is methyl.

In a specific aspect, R^(c) is hydrogen, C₁₋₃alkyl, or benzyl. Inanother specific aspect, R^(c) is hydrogen or benzyl

In a specific aspect, m is 1 or 2. In another specific aspect m is 1.

In yet another aspect, the invention provides a compound of formula(Ia):

wherein:

R¹ is C₄₋₁₀ alkyl, C₃₋₁₂cycloalkyl, or phenyl, wherein C₃₋₁₂cycloalkyland phenyl are each optionally substituted with one or two halo;

R² is selected from —C(O)R³, —C(O)NHR⁴, —C(O)OR⁵, and —S(O)₂R⁶;

R³, R⁴, and R⁵ are each independently C₁₋₆ alkyl substituted with one ortwo substituents selected from —OR^(a) and —S(O)₂R^(b);

R⁶ is C₁₋₃alkyl;

R^(a) is hydrogen or C₁₋₃alkyl;

R^(b) is C₁₋₃alkyl; and

m is 1 or 2;

or a pharmaceutically-acceptable salt thereof.

In still another aspect, the invention provides a compound of formula(Ib) or (Ic):

wherein R¹, R³, R⁷, and m take any of the values defined above.

The invention further provides the compounds of Examples 1-26 herein.

The chemical naming convention used herein is illustrated for thecompound of Example 1:

which is3-endo-(8-{2-[((S)-2,3-dihydroxypropionyl)-(2-ethylbutyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide.Alternatively, using the IUPAC conventions as implemented in AutoNomsoftware, (MDL Information Systems, GmbH, Frankfurt, Germany), thecompound is denoted3-((1R,3R,5S)-8-{2-[((S)-2,3-dihydroxy-propionyl)-(2-ethylbutyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamide.The names used herein therefore correspond to the IUPAC notation withthe endo orientation of the substituted phenyl group with respect to the8-azabicyclo[3.2.1]octane group indicated explicitly. All of thecompounds of the invention are in the endo orientation. For convenience,as used herein, the term “8-azabicyclooctane” means8-azabicyclo[3.2.1]octane.

In addition to the endo stereochemistry with respect to the bicyclogroup, the compounds of the invention may contain a chiral center in thesubstituents R¹ and R³. Accordingly, the invention includes racemicmixtures, pure stereoisomers, and stereoisomer-enriched mixtures of suchisomers, unless otherwise indicated. When the stereochemistry of acompound is specified, including both the orientation with respect tothe 8-azabicyclooctane group and the chirality in a substituent R¹and/or R³, it will be understood by those skilled in the art, that minoramounts of other stereoisomers may be present in the compositions of theinvention unless otherwise indicated, provided that any utility of thecomposition as a whole is not eliminated by the presence of such otherisomers.

DEFINITIONS

When describing the compounds, compositions and methods of theinvention, the following terms have the following meanings, unlessotherwise indicated.

The term “alkyl” means a monovalent saturated hydrocarbon group whichmay be linear or branched or combinations thereof. Unless otherwisedefined, such alkyl groups typically contain from 1 to 10 carbon atoms.Representative alkyl groups include, by way of example, methyl, ethyl,n-propyl (n-Pr), isopropyl (i-Pr), n-butyl (n-Bu), sec-butyl, isobutyl,tert-butyl, n-pentyl, n-hexyl, 2,2-dimethylpropyl, 2-methylbutyl,3-methylbutyl, 2-ethylbutyl, 2,2-dimethylpentyl, 2-propylpentyl, and thelike.

The term “cycloalkyl” means a monovalent saturated or partiallysaturated carbocyclic group which may be monocyclic or multicyclic.Unless otherwise defined, such cycloalkyl groups typically contain from3 to 12 carbon atoms. Representative cycloalkyl groups include, by wayof example, cyclopropyl (c-propyl), cyclobutyl (c-butyl), cyclopentyl(c-pentyl), cyclohexyl (c-hexyl), cycloheptyl (c-heptyl), cyclooctyl(c-octyl), adamantyl, cyclohexenyl, and the like.

The term “halo” means fluoro, chloro, bromo or iodo.

The term “compound” means a compound that was synthetically prepared orprepared in any other way, such as by in vivo metabolism.

The term “therapeutically effective amount” means an amount sufficientto effect treatment when administered to a patient in need of treatment.

The term “treatment” as used herein means the treatment of a disease,disorder, or medical condition in a patient, such as a mammal(particularly a human) which includes:

-   -   (a) preventing the disease, disorder, or medical condition from        occurring, i.e., prophylactic treatment of a patient;    -   (b) ameliorating the disease, disorder, or medical condition,        i.e., eliminating or causing regression of the disease,        disorder, or medical condition in a patient, including        counteracting the effects of other therapeutic agents;    -   (c) suppressing the disease, disorder, or medical condition,        i.e., slowing or arresting the development of the disease,        disorder, or medical condition in a patient; or    -   (d) alleviating the symptoms of the disease, disorder, or        medical condition in a patient.

The term “pharmaceutically-acceptable salt” means a salt prepared froman acid or base which is acceptable for administration to a patient,such as a mammal. Such salts can be derived frompharmaceutically-acceptable inorganic or organic acids and frompharmaceutically-acceptable bases. Typically,pharmaceutically-acceptable salts of compounds of the present inventionare prepared from acids.

Salts derived from pharmaceutically-acceptable acids include, but arenot limited to, acetic, adipic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,glycolic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, oxalic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic(1-hydroxy-2-naphthoic acid), naphthalene-1,5-disulfonic acid and thelike.

The term “amino-protecting group” means a protecting group suitable forpreventing undesired reactions at an amino nitrogen. Representativeamino-protecting groups include, but are not limited to, formyl; acylgroups, for example alkanoyl groups, such as acetyl andtri-fluoroacetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl(Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl(Bn), trityl (Tr), and 1,1-di-(4′-methoxyphenyl)methyl; silyl groups,such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS); andthe like.

General Synthetic Procedures

Compounds of the invention can be prepared from readily availablestarting materials using the following general methods and procedures.Although a particular aspect of the present invention is illustrated inthe schemes below, those skilled in the art will recognize that allaspects of the present invention can be prepared using the methodsdescribed herein or by using other methods, reagents and startingmaterials known to those skilled in the art. It will also be appreciatedthat where typical or preferred process conditions (i.e., reactiontemperatures, times, mole ratios of reactants, solvents, pressures,etc.) are given, other process conditions can also be used unlessotherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvent used, but such conditions can bedetermined by one skilled in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group, as well assuitable conditions for protection and deprotection, are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and G. M. Wuts, ProtectingGroups in Organic Synthesis, Third Edition, Wiley, New York, 1999, andreferences cited therein.

In one method of synthesis, compounds of the invention of formula (Id),in which R² is defined as —C(O)R³ or —C(O)R⁸, are prepared asillustrated in Scheme A. (The substituents and variables shown in thefollowing schemes have the definitions provided above unless otherwiseindicated).

In Scheme A, R⁹ represents R³ or R⁸, R^(9a) represents R³, a protectedform of R³, or R⁸, and L represents a leaving group, such as chloro, orR^(9a)C(O)-L represents a carboxylic acid or a carboxylate salt. Forexample, to prepare a compound in which R³ is —CH₂OH, a useful reagentis acetoxyacetyl chloride, in which R^(9a) is —CH₂OC(O)CH₃ and L ischloro. When R^(9a) is a protected form of R³, the reaction alsoincludes a deprotection step, which is not shown.

Optimal reaction conditions for the reaction of Scheme A may varydepending on the chemical properties of the reagent R^(9a)C(O)-L, as iswell known to those skilled in the art. For example, when L is a haloleaving group, such as chloro, the reaction is typically conducted bycontacting intermediate (II) with between about 1 and about 2equivalents of a compound of formula R^(9a)C(O)-L in an inert diluent,such as dichloromethane. Optionally, the reaction is conducted in thepresence of base, for example between about 2 and about 6 equivalents ofbase, such as N,N-diisopropylethylamine or triethylamine. Suitable inertdiluents also include 1,1,2,2-tetrachloroethane, tetrahydrofuran,dimethylacetamide, and the like. The reaction is typically conducted ata temperature in the range of about −50° C. to about 30° C. for about aquarter hour to about 16 hours, or until the reaction is substantiallycomplete.

When the reagent R^(9a)C(O)-L is a carboxylic acid or a carboxylatesalt, the reaction is typically conducted by contacting intermediate(II) with between about 1 and about 5 equivalents of the acidR^(9a)C(O)OH or the carboxylate salt, for example, R^(9a)C(O)OLi, in aninert diluent, optionally in the presence of an excess of base, both asdescribed above, and in the presence of between about 1 and about 6equivalents of an activating agent such as N,N-carbonyl diimidazole(CDI), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC). The reaction istypically conducted at a temperature in the range of about 25° C. toabout 100° C. for about 2 hours to about 16 hours, or until the reactionis substantially complete.

Compounds of the invention in which R² is —C(O)NHR⁴, —C(O)OR⁵, orS(O)₂R⁶ may be prepared by similar processes using reagents R⁴—N═C═O,R⁵OC(O)-L′ and R⁶—S(O)₂-L′, respectively, where L′ represents a haloleaving group, in place of R^(9a)C(O)-L.

A general procedure for the preparation of an intermediate of formula(II) is illustrated in Scheme B

where P¹ represents an amino-protecting group. In Scheme B, intermediate(IV) is reductively N-alkylated by reaction with the aldehyde (III) toprovide protected intermediate (V). The reaction is typically conductedby contacting intermediate (IV) with between about 1 and about 2equivalents of an aldehyde of formula (III) in a suitable inert diluent,such as dichloromethane, in the presence of between about 0.9 and about2 equivalents of a reducing agent. The reaction is typically conductedat a temperature in the range of about 0° C. to ambient temperature forabout a half hour to about 3 hours or until the reaction issubstantially complete. Typical reducing agents include sodiumtriacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride.The product (V) is isolated by conventional means. The deprotection of(V) uses standard procedures. For example, when the protecting group P¹is Boc, (V) is typically treated with an acid, such as trifluoroaceticacid to provide intermediate (II). When the protecting group isbenzyloxycarbonyl (Cbz), (V) may be deprotected by catalytichydrogenation, with, for example, a palladium hydroxide on carboncatalyst.

An exemplary process for the preparation of intermediates of formula(III′) where R⁷ is —CH₂—R¹ is illustrated in Scheme C:

where all the variables take the values defined above. First, anamino-protecting group is added to intermediate (VI) by conventionalprocedures to form intermediate (VII), which is oxidized, for example,in the presence of a sulfur trioxide pyridium complex, to provide anintermediate of formula (III′).

The 8-azabicyclooctyl-2-hydroxybenzamide intermediate (IV) may beprepared by the Suzuki coupling of the bicyclic vinyl boronate (XII)with the benzyloxy-bromo-benzamide (X) as shown in step (c) of Scheme Dbelow.

The benzamide intermediate (X) may be prepared from3-bromo-2-fluoro-benzonitrile (VIII) by the route shown in step (a) inwhich (VIII) is first converted to intermediate (IX), where Bn denotesthe protecting group benzyl, by reaction with benzyl alcohol. Thenitrile (IX) is then hydrolyzed to the corresponding amide to provideintermediate (X). The hydrolysis reaction may be performed by contacting(IX) with an excess of water in the presence of a platinumdialkylphosphonite catalyst, commonly termed Parkin's catalyst. Thereaction is typically performed at reflux temperature for about 2 toabout 20 hours or until the reaction is substantially complete.

The bicyclic vinyl boronate (XII) may be prepared by reaction of theprotected bicyclooctene intermediate (XI), where P¹ represents anamino-protecting group, typically Boc or benzyl, and —OTf representstrifluoromethane sulfonate (commonly triflate) withbis(pinacolato)diboron as shown in step (b). The reaction is typicallyconducted by contacting (XII) with between about 1 and about 1.2equivalents of bis(pinacolato)diboron in the presence of a catalyticamount of a palladium catalyst and a phosphine ligand, for example[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)(Pd(dppf)Cl₂) and 1,1′-bis(diphenylphosphino)ferrocene (dppf). Thereaction is typically conducted at a temperature between about 40 andabout 80° C. for between about 4 and about 20 hours or until thereaction is substantially complete.

The protected bicyclooctene intermediate (XI) used in step (b), where P¹is benzyl, is conveniently prepared from8-benzyl-8-azabicyclo[3.2.1]octan-3-one:

by contacting the octanone with between about 1 and about 1.5equivalents of N-phenyl-bis(trifluoromethanesulfonimide) and betweenabout 1 and about 1.5 equivalents of a base, such as sodiumbis(trimethylsilyl)amide. The reaction is typically conducted at atemperature between about −20 and about −10° C. for between about onehalf to about two hours, or until the reaction is substantiallycomplete.

To prepare intermediate (XI) in which P¹ is Boc, the benzyl-protectedoctanone is first converted to the Boc-protected form by reaction withdi-tert-butyl dicarbonate (commonly Boc₂O) and catalytic hydrogenation.The Boc-protected octanone is then reacted withN-phenyl-bis(trifluoromethanesulfonimide) and base as described above.The reaction of the Boc intermediate is typically conducted at atemperature, less than about −70° C., for between about 2 and about 5hours, or until the reaction is substantially complete.

Finally, the bicyclic vinyl boronate (XII) and benzamide intermediate(X) are coupled to provide the protected intermediate (XIII), which isreduced and deprotected in one or more steps, to provide the8-azabicyclooctyl-2-hydroxybenzamide intermediate (IV). The reaction istypically conducted by contacting (XII) with about 1 equivalent ofintermediate (X) in the presence of a palladium catalyst, for example,bis(triphenylphosphine)-palladium(II) chloride (PdCl₂(PPh₃)₂). Thereaction is typically conducted at reflux temperature for between about4 and about 20 hours or until the reaction is substantially complete.When P¹ is Boc, typically, the Boc protecting group is first removed byconventional treatment with trifluoroacetic acid and then thebicyclooctene is simultaneously reduced and deprotected by palladiumcatalyzed hydrogenation. When a benzyl protecting group is used for P¹,the double bond reduction and removal of both benzyl groups can beaccomplished in a single hydrogenation step.

An alternative process for the preparation of intermediate (IV) usingBoc protected intermediate (XII′) is illustrated in Scheme E:

in which the order of the Suzuki coupling and the conversion of thenitrile to the amide is reversed. As shown in Scheme E, and described inthe examples below, the 2-benzyloxy-3-bromo-benzonitrile intermediate(IX) is coupled to the bicyclic boronate (XII′) to form nitrileintermediate (XIV). In subsequent steps, the Boc group is deprotectedfrom the nitrile intermediate, the cyano group is hydrolyzed, andfinally the double bond is reduced and the benzyl protecting group isremoved to form the 2-hydroxybenzamide (IV).

Yet another alternative process for the preparation of intermediate (IV)is illustrated in Scheme F:

First, the benzyl-protected bicyclooctene intermediate (XI′) is reactedwith 2-butoxy-3-bromo-benzonitrile, the butoxy analog of intermediate(IX) to form the nitrile intermediate (XV). The reaction is typicallyconducted by contacting intermediate (XI′) with between about 1 andabout 1.5 equivalents of 2-butoxy-3-bromo-benzonitrile in an inertdiluent, such as tetrahydrofuran, in the presence of between about 1 andabout 1.5 equivalents of isopropylmagnesium chloride and a transitionmetal catalyst. The reaction is typically performed at refluxtemperature for about one-half to about three hours or until thereaction is substantially complete. Intermediate (XV) is refluxed in anacidic solution to simultaneously hydrolyze the cyano group to the amideand remove the tert-butyl hydroxy-protecting group to provideintermediate (XVI). Finally, (XVI) is converted to the benzamide product(IV), in a single step, by reaction with between about 10 and about 15equivalents of ammonium formate, in the presence of a palladiumcatalyst, which simultaneously reduces the bicyclooctene and removes thebenzyl amino-protecting group.

Further details regarding specific reaction conditions and otherprocedures for preparing representative compounds of the invention orintermediates thereto are described in the examples below.

Accordingly, in a method aspect, the invention provides a process forpreparing a compound of formula (Id), or a salt or protected derivativethereof, the process comprising reacting a compound of formula (II) witha compound of formula R^(9a)C(O)-L, and optionally removing a protectinggroup, to provide a compound of formula (Id), or a salt or protectedderivative thereof.

In an additional aspect, the invention provides a compound of formula(II) and a compound of formula (IV), wherein the variables R⁷ and m takeany of the values described in aspects of the invention disclosed above.

Pharmaceutical Compositions

The 8-azabicyclooctane-2-hydroxybenzamide compounds of the invention aretypically administered to a patient in the form of a pharmaceuticalcomposition or formulation. Such pharmaceutical compositions may beadministered to the patient by any acceptable route of administrationincluding, but not limited to, oral, rectal, vaginal, nasal, inhaled,topical (including transdermal) and parenteral modes of administration.

Accordingly, in one of its compositions aspects, the invention isdirected to a pharmaceutical composition comprising apharmaceutically-acceptable carrier or excipient and a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof. Optionally, such pharmaceutical compositionsmay contain other therapeutic and/or formulating agents if desired. Whendiscussing compositions, the “compound of the invention” may also bereferred to herein as the “active agent”. As used herein, the term“compound of the invention” is intended to include compounds of formula(I) as well as the species embodied in formulas (Ia), (Ib), (Ic), and(Id). “Compound of the invention” includes, in addition,pharmaceutically-acceptable salts and solvates of the compound unlessotherwise indicated.

The pharmaceutical compositions of the invention typically contain atherapeutically effective amount of a compound of the present inventionor a pharmaceutically-acceptable salt thereof. Typically, suchpharmaceutical compositions will contain from about 0.1 to about 95% byweight of the active agent; preferably, from about 5 to about 70% byweight; and more preferably from about 10 to about 60% by weight of theactive agent.

Any conventional carrier or excipient may be used in the pharmaceuticalcompositions of the invention. The choice of a particular carrier orexcipient, or combinations of carriers or excipients, will depend on themode of administration being used to treat a particular patient or typeof medical condition or disease state. In this regard, the preparationof a suitable pharmaceutical composition for a particular mode ofadministration is well within the scope of those skilled in thepharmaceutical arts. Additionally, the carriers or excipients used inthe pharmaceutical compositions of this invention arecommercially-available. By way of further illustration, conventionalformulation techniques are described in Remington: The Science andPractice of Pharmacy, 20^(th) Edition, Lippincott Williams & White,Baltimore, Md. (2000); and H. C. Ansel et al., Pharmaceutical DosageForms and Drug Delivery Systems, 7^(th) Edition, Lippincott Williams &White, Baltimore, Md. (1999).

Representative examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, the following:sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose, such as microcrystalline cellulose,and its derivatives, such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients, such as cocoa butter and suppository waxes; oils, suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil and soybean oil; glycols, such as propylene glycol; polyols,such as glycerin, sorbitol, mannitol and polyethylene glycol; esters,such as ethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; phosphatebuffer solutions; and other non-toxic compatible substances employed inpharmaceutical compositions.

Pharmaceutical compositions are typically prepared by thoroughly andintimately mixing or blending the active agent with apharmaceutically-acceptable carrier and one or more optionalingredients. The resulting uniformly blended mixture can then be shapedor loaded into tablets, capsules, pills and the like using conventionalprocedures and equipment.

The pharmaceutical compositions of the invention are preferably packagedin a unit dosage form. The term “unit dosage form” refers to aphysically discrete unit suitable for dosing a patient, i.e., each unitcontaining a predetermined quantity of active agent calculated toproduce the desired therapeutic effect either alone or in combinationwith one or more additional units. For example, such unit dosage formsmay be capsules, tablets, pills, and the like, or unit packages suitablefor parenteral administration.

In one embodiment, the pharmaceutical compositions of the invention aresuitable for oral administration. Suitable pharmaceutical compositionsfor oral administration may be in the form of capsules, tablets, pills,lozenges, cachets, dragees, powders, granules; or as a solution or asuspension in an aqueous or non-aqueous liquid; or as an oil-in-water orwater-in-oil liquid emulsion; or as an elixir or syrup; and the like;each containing a predetermined amount of a compound of the presentinvention as an active ingredient.

When intended for oral administration in a solid dosage form (i.e., ascapsules, tablets, pills and the like), the pharmaceutical compositionsof the invention will typically comprise the active agent and one ormore pharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate. Optionally or alternatively, such solid dosageforms may also comprise: fillers or extenders, such as starches,microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/orsilicic acid; binders, such as carboxymethylcellulose, alginates,gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, suchas glycerol; disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and/or sodium carbonate; solution retarding agents, such as paraffin;absorption accelerators, such as quaternary ammonium compounds; wettingagents, such as cetyl alcohol and/or glycerol monostearate; absorbents,such as kaolin and/or bentonite clay; lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, and/or mixtures thereof; coloring agents; and buffering agents.

Release agents, wetting agents, coating agents, sweetening, flavoringand perfuming agents, preservatives and antioxidants can also be presentin the pharmaceutical compositions of the invention. Examples ofpharmaceutically-acceptable antioxidants include: water-solubleantioxidants, such as ascorbic acid, cysteine hydrochloride, sodiumbisulfate, sodium metabisulfate, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate,alpha-tocopherol, and the like; and metal-chelating agents, such ascitric acid, ethylenediamine tetraacetic acid, sorbitol, tartaric acid,phosphoric acid, and the like. Coating agents for tablets, capsules,pills and like, include those used for enteric coatings, such ascellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid-methacrylic acid estercopolymers, cellulose acetate trimellitate, carboxymethyl ethylcellulose, hydroxypropyl methyl cellulose acetate succinate, and thelike.

Pharmaceutical compositions of the invention may also be formulated toprovide slow or controlled release of the active agent using, by way ofexample, hydroxypropyl methyl cellulose in varying proportions; or otherpolymer matrices, liposomes and/or microspheres. In addition, thepharmaceutical compositions of the invention may optionally containopacifying agents and may be formulated so that they release the activeingredient only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active agent can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Suitable liquid dosage forms for oral administration include, by way ofillustration, pharmaceutically-acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. Liquid dosage formstypically comprise the active agent and an inert diluent, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (esp., cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. Suspensions, inaddition to the active ingredient, may contain suspending agents suchas, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

The compounds of this invention can also be administered parenterally(e.g. by intravenous, subcutaneous, intramuscular or intraperitonealinjection). For parenteral administration, the active agent is typicallyadmixed with a suitable vehicle for parenteral administration including,by way of example, sterile aqueous solutions, saline, low molecularweight alcohols such as propylene glycol, polyethylene glycol, vegetableoils, gelatin, fatty acid esters such as ethyl oleate, and the like.Parenteral formulations may also contain one or more anti-oxidants,solubilizers, stabilizers, preservatives, wetting agents, emulsifiers,buffering agents, or dispersing agents. These formulations may berendered sterile by use of a sterile injectable medium, a sterilizingagent, filtration, irradiation, or heat.

Alternatively, the pharmaceutical compositions of the invention areformulated for administration by inhalation. Suitable pharmaceuticalcompositions for administration by inhalation will typically be in theform of an aerosol or a powder. Such compositions are generallyadministered using well-known delivery devices, such as a metered-doseinhaler, a dry powder inhaler, a nebulizer or a similar delivery device.

When administered by inhalation using a pressurized container, thepharmaceutical compositions of the invention will typically comprise theactive ingredient and a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas.Additionally, the pharmaceutical composition may be in the form of acapsule or cartridge (made, for example, from gelatin) comprising acompound of the invention and a powder suitable for use in a powderinhaler. Suitable powder bases include, by way of example, lactose orstarch.

The compounds of the invention can also be administered transdermallyusing known transdermal delivery systems and excipients. For example,the active agent can be admixed with permeation enhancers, such aspropylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-onesand the like, and incorporated into a patch or similar delivery system.Additional excipients including gelling agents, emulsifiers and buffers,may be used in such transdermal compositions if desired.

If desired, the compounds of this invention may be administered incombination with one or more other therapeutic agents. In thisembodiment, a compound of this invention is either physically mixed withthe other therapeutic agent to form a composition containing bothagents; or each agent is present in separate and distinct compositionswhich are administered to the patient simultaneously or sequentially.

For example, a compound of formula I can be combined with secondtherapeutic agent using conventional procedures and equipment to form acomposition comprising a compound of formula I and a second therapeuticagent. Additionally, the therapeutic agents may be combined with apharmaceutically acceptable carrier to form a pharmaceutical compositioncomprising a compound of formula I, a second therapeutic agent and apharmaceutically acceptable carrier. In this embodiment, the componentsof the composition are typically mixed or blended to create a physicalmixture. The physical mixture is then administered in a therapeuticallyeffective amount using any of the routes described herein.Alternatively, the therapeutic agents may remain separate and distinctbefore administration to the patient. In this embodiment, the agents arenot physically mixed together before administration but are administeredsimultaneously or at separate times as separate compositions. Suchcompositions can be packaged separately or may be packaged together as akit. The two therapeutic agents in the kit may be administered by thesame route of administration or by different routes of administration.

Any therapeutic agent compatible with the compounds of the presentinvention may be used as the second therapeutic agent. In particular,prokinetic agents acting via mechanisms other than mu opioid receptorantagonism may be used in combination with the present compounds. Forexample, 5-HT₄ receptor agonists, such as tegaserod, renzapride,mosapride, prucalopride, 1-isopropyl-1H-indazole-3-carboxylic acid{(1S,3R,5R)-8-[2-(4-acetylpiperazin-1-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}amide,1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid{(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide,and4-(4-{[(2-isopropyl-1H-benzoimidazole-4-carbonyl)amino]methyl}-piperidin-1-ylmethyl)piperidine-1-carboxylicacid methyl ester and pharmaceutically-acceptable salts thereof may beused as the second therapeutic agent.

Additional useful prokinetic agents and other agents forgastrointestinal disorders include, but are not limited to, 5-HT₃receptor agonists (e.g. pumosetrag), 5-HT_(1A) receptor antagonists(e.g. AGI 001), alpha-2-delta ligands (e.g. PD-217014), chloride channelopeners (e.g. lubiprostone), dopamine antagonists (e.g. itopride,metaclopramide, domperidone), GABA-B agonists (e.g. baclofen, AGI 006),kappa opioid agonists (e.g. asimadoline), muscarinic M₁ and M₂antagonists (e.g. acotiamide), motilin agonists (e.g. mitemcinal),guanylate cyclase activators (e.g. MD-1100) and ghrelin agonists (e.g.Tzp 101, RC 1139).

In addition, the compounds of the invention can be combined with opioidtherapeutic agents. Such opioid agents include, but are not limited to,morphine, pethidine, codeine, dihydrocodeine, oxycontin, oxycodone,hydrocodone, sufentanil, fentanyl, remifentanil, buprenorphine,methadone, and heroin.

Numerous additional examples of such therapeutic agents are known in theart and any such known therapeutic agents may be employed in combinationwith the compounds of this invention. Secondary agent(s), when included,are present in a therapeutically effective amount, i.e. in any amountthat produces a therapeutically beneficial effect when co-administeredwith a compound of the invention. Suitable doses for the othertherapeutic agents administered in combination with a compound of theinvention are typically in the range of about 0.05 μg/day to about 100mg/day.

Accordingly, the pharmaceutical compositions of the invention optionallyinclude a second therapeutic agent as described above.

The following examples illustrate representative pharmaceuticalcompositions of the present invention:

Formulation Example A Hard Gelatin Capsules for Oral Administration

A compound of the invention (50 g), spray-dried lactose (200 g) andmagnesium stearate (10 g) are thoroughly blended. The resultingcomposition is loaded into a hard gelatin capsule (260 mg of compositionper capsule).

Formulation Example B Hard Gelatin Capsules for Oral Administration

A compound of the invention (20 mg), starch (89 mg), microcrystallinecellulose (89 mg), and magnesium stearate (2 mg) are thoroughly blendedand then passed through a No. 45 mesh U.S. sieve. The resultingcomposition is loaded into a hard gelatin capsule (200 mg of compositionper capsule).

Formulation Example C Gelatin Capsules for Oral Administration

A compound of the invention (10 mg), polyoxyethylene sorbitan monooleate(50 mg), and starch powder (250 mg) are thoroughly blended and thenloaded into a gelatin capsule (310 mg of composition per capsule).

Formulation Example D Tablets for Oral Administration

A compound of the invention (5 mg), starch (50 mg), and microcrystallinecellulose (35 mg) are passed through a No. 45 mesh U.S. sieve and mixedthoroughly. A solution of polyvinylpyrrolidone (10 wt % in water, 4 mg)is mixed with the resulting powders, and this mixture is then passedthrough a No. 14 mesh U.S. sieve. The granules so produced are dried at50-60° C. and passed through a No. 18 mesh U.S. sieve. Sodiumcarboxymethyl starch (4.5 mg), magnesium stearate (0.5 mg) and talc (1mg), which have previously been passed through a No. 60 mesh U.S. sieve,are then added to the granules. After mixing, the mixture is compressedon a tablet machine to afford a tablet weighing 100 mg.

Formulation Example E Tablets for Oral Administration

A compound of the invention (25 mg), microcrystalline cellulose (400mg), fumed silicon dioxide (10 mg), and stearic acid (5 mg) arethoroughly blended and then compressed to form tablets (440 mg ofcomposition per tablet).

Formulation Example F Single-Scored Tablets for Oral Administration

A compound of the invention (15 mg), cornstarch (50 mg), croscarmellosesodium (25 mg), lactose (120 mg), and magnesium stearate (5 mg) arethoroughly blended and then compressed to form single-scored tablet (215mg of compositions per tablet).

Formulation Example G Suspension for Oral Administration

The following ingredients are thoroughly mixed to form a suspension fororal administration containing 100 mg of active ingredient per 10 mL ofsuspension:

Ingredients Amount Compound of the invention 0.1 g Fumaric acid 0.5 gSodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 gGranulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum k(Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5 mg Distilledwater q.s. to 100 mL

Formulation Example H Dry Powder Composition

A micronized compound of the invention (1 mg) is blended with lactose(25 mg) and then loaded into a gelatin inhalation cartridge. Thecontents of the cartridge are administered using a powder inhaler.

Formulation Example J Injectable Formulation

A compound of the invention (0.1 g) is blended with 0.1 M sodium citratebuffer solution (15 mL). The pH of the resulting solution is adjusted topH 6 using 1 N aqueous hydrochloric acid or 1 N aqueous sodiumhydroxide. Sterile normal saline in citrate buffer is then added toprovide a total volume of 20 mL.

It will be understood that any form of the compounds of the invention,(i.e. free base, pharmaceutical salt, or solvate) that is suitable forthe particular mode of administration, can be used in the pharmaceuticalcompositions discussed above.

Utility

The 8-azabicyclooctane compounds of the invention are antagonists at themu opioid receptor and therefore are expected to be useful for treatingmedical conditions mediated by mu opioid receptors or associated with muopioid receptor activity, i.e. medical conditions which are amelioratedby treatment with a mu opioid receptor antagonist. In particular, thecompounds of the invention are expected to be useful for treatingadverse effects associated with use of opioid analgesics, i.e. symptomssuch as constipation, decreased gastric emptying, abdominal pain,bloating, nausea, and gastroesophageal reflux, termed collectivelyopioid-induced bowel dysfunction. The mu opioid receptor antagonists ofthe invention are also expected to be useful for treating post-operativeileus, a disorder of reduced motility of the gastrointestinal tract thatoccurs after abdominal or other surgery. In addition, it has beensuggested that mu opioid receptor antagonist compounds may be used forreversing opioid-induced nausea and vomiting. Further, those mu opioidreceptor antagonists exhibiting some central penetration may be usefulin the treatment of dependency on, or addiction to, narcotic drugs,alcohol, or gambling, or in preventing, treating, and/or amelioratingobesity.

Since compounds of the invention increase motility of thegastrointestinal (GI) tract in animal models, the compounds are expectedto be useful for treating disorders of the GI tract caused by reducedmotility in mammals, including humans. Such GI motility disordersinclude, by way of illustration, chronic constipation,constipation-predominant irritable bowel syndrome (C-IBS), diabetic andidiopathic gastroparesis, and functional dyspepsia.

In one aspect, therefore, the invention provides a method of increasingmotility of the gastrointestinal tract in a mammal, the methodcomprising administering to the mammal a therapeutically effectiveamount of a pharmaceutical composition comprising apharmaceutically-acceptable carrier and a compound of the invention.

When used to treat disorders of reduced motility of the GI tract orother conditions mediated by mu opioid receptors, the compounds of theinvention will typically be administered orally in a single daily doseor in multiple doses per day, although other forms of administration maybe used. For example, particularly when used to treat post-operativeileus, the compounds of the invention may be administered parenterally.The amount of active agent administered per dose or the total amountadministered per day will typically be determined by a physician, in thelight of the relevant circumstances, including the condition to betreated, the chosen route of administration, the actual compoundadministered and its relative activity, the age, weight, and response ofthe individual patient, the severity of the patient's symptoms, and thelike.

Suitable doses for treating disorders of reduced motility of the GItract or other disorders mediated by mu opioid receptors will range fromabout 0.0007 to about 20 mg/kg/day of active agent, including from about0.0007 to about 1.4 mg/kg/day. For an average 70 kg human, this wouldamount to from about 0.05 to about 100 mg per day of active agent.

In one aspect of the invention, the compounds of the invention are usedto treat opioid-induced bowel dysfunction. When used to treatopioid-induced bowel dysfunction, the compounds of the invention willtypically be administered orally in a single daily dose or in multipledoses per day. Preferably, the dose for treating opioid-induced boweldysfunction will range from about 0.05 to about 100 mg per day.

In another aspect of the invention, the compounds of the invention areused to treat post-operative ileus. When used to treat post-operativeileus, the compounds of the invention will typically be administeredorally or intravenously in a single daily dose or in multiple doses perday. Preferably, the dose for treating post-operative ileus will rangefrom about 0.05 to about 100 mg per day.

The invention also provides a method of treating a mammal having adisease or condition associated with mu opioid receptor activity, themethod comprising administering to the mammal a therapeuticallyeffective amount of a compound of the invention or of a pharmaceuticalcomposition comprising a compound of the invention.

As described above, compounds of the invention are mu opioid receptorantagonists. The invention further provides, therefore, a method ofantagonizing a mu opioid receptor in a mammal, the method comprisingadministering a compound of the invention to the mammal.

The mu opioid receptor antagonists of the invention are optionallyadministered in combination with another therapeutic agent or agents, inparticular, in combination with prokinetic agents acting via non-muopioid mechanisms. Accordingly, in another aspect, the methods andcompositions of the invention further comprise a therapeuticallyeffective amount of another prokinetic agent.

In addition, the compounds of the invention are also useful as researchtools for investigating or studying biological systems or samples havingmu opioid receptors, or for discovering new compounds having mu opioidreceptor activity. Any suitable biological system or sample having muopioid receptors may be employed in such studies which may be conductedeither in vitro or in vivo. Representative biological systems or samplessuitable for such studies include, but are not limited to, cells,cellular extracts, plasma membranes, tissue samples, mammals (such asmice, rats, guinea pigs, rabbits, dogs, pigs, etc.) and the like. Theeffects of contacting a biological system or sample comprising a muopioid receptor with a compound of the invention are determined usingconventional procedures and equipment, such as the radioligand bindingassay and functional assay described herein or other functional assaysknown in the art. Such functional assays include, but are not limitedto, ligand-mediated changes in intracellular cyclic adenosinemonophosphate (cAMP), ligand-mediated changes in activity of the enzymeadenylyl cyclase, ligand-mediated changes in incorporation of analogs ofguanosine triphosphate (GTP), such as [³⁵S]GTPγS (guanosine5′-O-(γ-thio)triphosphate) or GTP—Eu, into isolated membranes viareceptor catalyzed exchange of GTP analogs for GDP analogs, andligand-mediated changes in free intracellular calcium ions. A suitableconcentration of a compound of the invention for such studies typicallyranges from about 1 nanomolar to about 500 nanomolar.

When using compounds of the invention as research tools for discoveringnew compounds have mu opioid receptor activity, binding or functionaldata for a test compound or a group of test compounds is compared to themu opioid receptor binding or functional data for a compound of theinvention to identify test compounds that have superior binding orfunctional activity, if any. This aspect of the invention includes, asseparate embodiments, both the generation of comparison data (using theappropriate assays) and the analysis of the test data to identify testcompounds of interest.

Among other properties, compounds of the invention have been found toexhibit potent binding to mu opioid receptors and little or no agonismin mu receptor functional assays. Therefore, the compounds of theinvention are potent mu opioid receptor antagonists. Further, compoundsof the invention have demonstrated predominantly peripheral activity ascompared with central nervous system activity in animal models.Therefore, these compounds can be expected to reverse opioid-inducedreductions in GI motility without interfering with the beneficialcentral effects of analgesia. These properties, as well as the utilityof the compounds of the invention, can be demonstrated using various invitro and in vivo assays well-known to those skilled in the art.Representative assays are described in further detail in the followingexamples.

EXAMPLES

The following synthetic and biological examples are offered toillustrate the invention, and are not to be construed in any way aslimiting the scope of the invention. In the examples below, thefollowing abbreviations have the following meanings unless otherwiseindicated. Abbreviations not defined below have their generally acceptedmeanings.

-   -   AcOH=acetic acid    -   Boc=tert-butoxycarbonyl    -   (Boc)₂O=di-tert-butyl dicarbonate    -   DCM=dichloromethane    -   DIPEA=N,N-diisopropylethylamine    -   DMF=N,N-dimethylformamide    -   DMSO=dimethyl sulfoxide    -   EtOAc=ethyl acetate    -   EtOH=ethanol    -   HATU=N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium        hexafluorophosphate    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran

Reagents (including secondary amines) and solvents were purchased fromcommercial suppliers (Aldrich, Fluka, Sigma, etc.), and used withoutfurther purification. Reactions were run under nitrogen atmosphere,unless noted otherwise. Progress of reaction mixtures was monitored bythin layer chromatography (TLC), analytical high performance liquidchromatography (anal. HPLC), and mass spectrometry, the details of whichare given below and separately in specific examples of reactions.Reaction mixtures were worked up as described specifically in eachreaction; commonly they were purified by extraction and otherpurification methods such as temperature-, and solvent-dependentcrystallization, and precipitation. In addition, reaction mixtures wereroutinely purified by preparative HPLC: a general protocol is describedbelow. Characterization of reaction products was routinely carried outby mass and ¹H-NMR spectrometry. For NMR measurement, samples weredissolved in deuterated solvent (CD₃OD, CDCl₃, or DMSO-d₆), and ¹H-NMRspectra were acquired with a Varian Gemini 2000 instrument (400 MHz)under standard observation conditions. Mass spectrometric identificationof compounds was performed by an electrospray ionization method (ESMS)with an Applied Biosystems (Foster City, Calif.) model API 150 EXinstrument or an Agilent (Palo Alto, Calif.) model 1200 LC/MSDinstrument.

Preparation 1: 2-Benzyloxy-3-bromobenzonitrile

To a flask containing sodium hydride (1.44 g, 60.0 mmol) suspended inDMF (60 mL, 800 mmol) at 0° C. was added benzyl alcohol (6.21 mL, 60.0mmol) over 5 min. The reaction mixture was stirred at 0° C. for 30 minand then 3-bromo-2-fluorobenzonitrile (10.0 g, 50.0 mmol) in DMF (20 mL)was added. The reaction mixture was warmed to room temperature andstirred at 80° C. for 2 h, cooled to room temperature, and extractedwith ethyl acetate (150 mL) and water (150 mL) The organic layer waswashed with water (150 mL) and brine (150 mL), collected, dried overanhydrous sodium sulfate, filtered, and concentrated. The crude productwas suspended with ethyl acetate:hexanes (1:3; 50 mL). The resultingsuspension was stirred vigorously for 1 h, filtered, and dried. Themother liquor was concentrated and recrystallized. The crystals werecombined and dried under vacuum to give the title compound (10.3 g).

¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.04 (dd, J=1.6, 8.2 Hz, 1H), 7.87(dd, J=1.6, 7.6 Hz, 1H), 7.56-7.51 (m, 2H), 7.47-7.37 (m, 3H), 7.29 (t,J=7.9 Hz, 1H), 5.20 (s, 1H).

Preparation 2: 2-Benzyloxy-3-bromobenzamide

The product of Preparation 1 (10.3 g, 0.0357 mol) was dissolved inethanol (20 mL, 0.4 mol), water (3.2 mL, 0.18 mol) and 1,4-dioxane (4mL, 0.05 mol). hydrido(dimethylphosphoniousacid-kP)[hydrogenbis(dimethylphosphinito-kP)]platinum (II) (30 mg, 0.00007 mol) was addedand the reaction mixture was heated to reflux overnight. To the hotsolution was added water (˜25 mL). The reaction mixture was cooled toroom temperature. The resulting crystals were filtered, dissolved inethyl acetate, dried with sodium sulfate, filtered, and evaporated togive a solid (9.1 g). The initial filtrate was evaporated to ˜30 mL andcooled at 0° C. for 2 h. The resulting crystals were filtered and driedto provide additional product (1.65 g). ¹H NMR (DMSO-d₆, 300 MHz) δ(ppm): 7.79 (br, 1H) 7.71 (dd, J=1.6, 8.0 Hz, 1H), 7.62 (br, 1H),7.52-7.46 (m, 3H), 7.40-7.30 (m, 3H), 7.29 (t, J=7.8 Hz, 1H), 4.96 (s,1H).

Preparation 3:3-Trifluoromethanesulfonyloxy-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylicacid tert-butyl ester

A solution of 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (15.8 g, 70.0 mmol) and THF (150 mL) was cooled to −78°C. and 1.0 M sodium hexamethyldisilazane in THF (84 mL) was addeddropwise over 5 min. The reaction mixture was stirred for 1 h and thenN-phenylbis(trifluoromethane-sulphonimide) (25.0 g, 70.0 mmol) was addedand the reaction mixture was stirred for 1 h. The solution was warmed toroom temperature, 1.0 N NaOH (100 mL) was added, and the reactionmixture was stirred for 15 min. Approximately 75 mL of solvent wasevaporated. The resulting solution was diluted with ethylacetate:hexanes (100 mL:100 mL) and water (100 mL), extracted and washedwith 1.0 N NaOH (2×200 mL). The organic layer was washed with saturatedNaCl solution (200 mL). The organic layer was collected, dried overanhydrous sodium sulfate, filtered, and concentrated to give the titlecompound (18.2 g) as a dark oil, which was used without furtherpurification.

Preparation 4:3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylicacid tert-butyl ester

The product of Preparation 3 (7.65 g, 0.0214 mol) was dissolved in1,4-dioxane (75 mL, 0.96 mol). To the reaction mixture was addedbis(pinacolato)diboron (5.71 g, 0.0225 mol), and potassium acetate (6.30g, 0.0642 mol), 1,1′-bis(diphenylphosphino)-ferrocene (0.5 g, 0.8 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II),complex with dichloromethane (1:1) (0.5 g, 0.6 mmol). The reactionmixture was purged with nitrogen, stirred at 80° C. overnight, andcooled to room temperature. The solution was filtered through Celite andconcentrated. The crude product was purified by flash columnchromatography eluting with (5-10%) ethyl acetate in hexanes to give thetitle compound (4.2 g) as an oil.

Preparation 5: 3-endo-(8-Azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamidea. 3-(8-Azabicyclo[3.2.1]oct-2-en-3-yl)-2-benzyloxybenzamide (A) and3-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-2-hydroxybenzamide (B)

To a flask was added 2-benzyloxy-3-bromobenzamide (1.60 g, 5.23 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylicacid tert-butyl ester (1.75 g, 5.23 mmol), THF (30 mL), 2.0 M sodiumcarbonate in water (10.4 mL), and bis(triphenylphosphine)palladium (II)chloride (92 mg, 0.13 mmol). The resulting mixture was purged withnitrogen, heated to reflux overnight, and cooled to room temperature.The reaction mixture was then concentrated, diluted with DCM (25 mL) andwashed with water (25 mL) The organic layer was collected, dried overanhydrous sodium sulfate, filtered, and concentrated. To the reactionmixture was added DCM (10 mL) and TFA (10 mL) and the mixture wasstirred at room temperature for 1 h, concentrated, and purified bypreparative HPLC to give a mixture of the title compounds as their TFAsalts. (A): (m/z): [M+H]⁺ calcd for C₂₁H₂₂N₂O₂, 335.17. found 336.0.(B): (m/z): [M+H]⁺ calcd for C₁₄H₁₆N₂O₂, 245.12. found 245.6.

b. 3-endo-(8-Azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide

To a flask under an atmosphere of nitrogen was added 10% Pd/C (0.1:0.9,palladium:carbon black, 0.040 g). The product of the previous step,3-(8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-2-benzyloxybenzamide TFA salt(0.400 g, 0.892 mmol) and3-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-2-hydroxybenzamide TFA salt (0.220g, 0.614 mmol) in methanol (10 mL) was added and the reaction mixturewas stirred under an atmosphere of hydrogen overnight, filtered throughCelite, concentrated, and purified by preparative HPLC to provide thetitle compound as its TFA salt (0.346 g). (m/z): [M+H]⁺ calcd forC₁₄H₁₈N₂O₂, 247.14. found 247.2.

Preparation 6: 3-endo-(8-Azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamidea.3-(2-Benzyloxy-3-cyanophenyl)-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylicacid tert-butyl ester

To a flask was added 2-benzyloxy-3-bromobenzonitrile (1.29 g, 4.47mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylicacid tert-butyl ester (1.50 g, 4.47 mmol), and THF (30 mL), 2.0 M sodiumcarbonate in water (8.95 mL), and bis(triphenylphosphine)palladium(II)chloride (78 mg, 0.11 mmol). The reaction mixture was purged withnitrogen, heated to reflux overnight, cooled to room temperature, andconcentrated. The resulting solution was diluted with DCM (25 mL) andwashed with water (25 mL) The organic layer was collected, dried overanhydrous sodium sulfate, filtered, and concentrated. The crude productwas purified by flash column chromatography eluting with ethyl acetatein hexanes (0-50%) to give partially purified product (1.2 g). (m/z):[M+H]⁺ calcd for C₂₆H₂₈N₂O₃ 416.21. (-tert-butyl 361.2). found 361;(-Boc 317.2). found 317.

b. 3-(8-Azabicyclo[3.2.1]oct-2-en-3-yl)-2-benzyloxybenzamide

To the product of the previous step (1.20 g, 0.00287 mol) in DCM (10 mL)was added TFA (10 mL). The reaction mixture was stirred for 1 h,concentrated, diluted with ethanol (2×20 mL), and concentrated. Ethanol(10 mL) and water (4 mL) were added followed byhydrido(dimethylphosphonious acid-kP)[hydrogenbis(dimethylphosphinito-kP)]platinum (II) (20 mg, 0.05 mmol). Thereaction mixture was heated at 75° C. overnight, cooled to roomtemperature, concentrated, and purified by preparative HPLC to give thetitle compound as its TFA salt (0.520 g). (m/z): [M+H]⁺ calcd forC₂₁H₂₂N₂O₂, 335.17. found 336.0.

c. 3-endo-(8-Azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide

To a flask under an atmosphere of nitrogen was added 10% Pd/C (0.1:0.9,palladium:carbon black, 0.050 g). The product of the previous step(0.520 g, 1.16 mmol) was added and the reaction mixture was stirredunder an atmosphere of hydrogen overnight, filtered through Celite,concentrated, and purified by preparative HPLC to provide the titlecompound as its TFA salt (0.310 g). (m/z): [M+H]⁺ calcd for C₁₄H₁₈N₂O₂,247.14. found 247.2.

Preparation 7: 3-endo-(8-Azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamidea.8-Benzyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene

Trifluoro-methanesulfonic acid 8-benzyl-8-azabicyclo[3.2.1]oct-2-en-3-ylester (13.2 g, 0.0380 mol) was dissolved in 1,4-dioxane (200 mL, 2 mol)and bis(pinacolato)diboron (10.1 g, 0.0399 mol), potassium acetate (11.2g, 0.114 mol), 1,1′-bis(diphenylphosphino)ferrocene (0.8 g, 0.002 mol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexwith dichloromethane (1:1) (0.9 g, 0.001 mol) was added. The reactionmixture was purged with nitrogen and stirred at 80° C. overnight. Thereaction mixture was cooled to room temperature, filtered throughCelite, concentrated, and purified by flash column chromatographyeluting with dichloromethane to give the title intermediate as a brownoil (6.0 g).

b. 8-Benzyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)-2-benzyloxybenzamide

To a flask was added 2-benzyloxy-3-bromobenzamide (3.8 g, 12 mmol), theproduct of the previous step (4.0 g, 12 mmol), THF (80 mL) and 2.0 Msodium carbonate in water (24.6 mL) followed bybis(triphenylphosphine)palladium(II) chloride (220 mg, 0.31 mmol). Thereaction mixture was purged with nitrogen and heated to refluxovernight. The reaction mixture was cooled to room temperature,concentrated, diluted with ethyl acetate (50 mL) and washed with water(50 mL). The organic layer was collected, dried over anhydrous sodiumsulfate, filtered, concentrated, and purified by flash columnchromatography eluting with dichloromethane:methanol (1% to 4% gradientwith 0.5% triethylamine) to give partially purified product (5.1 g).(m/z): [M+H]⁺ calcd for C₂₈H₂₈N₂O₂, 445.22. found 445.2.

c. 3-endo-(8-Azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide

To a flask under an atmosphere of nitrogen was added Pearlman's Catalyst(0.1:0.4, palladium hydroxide:carbon black, 0.500 g) and then theproduct of the previous step (4.0 g, 0.0094 mol) and trifluoroaceticacid (0.92 mL) in methanol (40 mL). The reaction mixture was stirredunder hydrogen (30 psi) overnight, filtered through Celite, concentratedand purified by preparative HPLC to give the title compound as its TFAsalt. (530 mg) and3-exo-(8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide (90 mg). (m/z):[M+H]⁺ calcd for C₁₄H₁₈N₂O₂, 247.14. found 247.2.

Preparation 8:3-endo-(8-[2-(2-Ethylbutylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl-2-hydroxybenzamidea. 2-(2-Ethylbutylamino)ethanol

A mixture of 3-bromomethyl-pentane (6.0 g, 36.4 mmol) and ethanolamine(13 mL, 218 mmol) in ethanol (45 mL) was heated at 75° C. for 16 h. Thereaction mixture was concentrated and the resulting residue was dilutedwith DCM (70 mL). The organic layer was partitioned with water (70 mL)and the aqueous layer extracted with DCM. Combined organic layers, driedover magnesium sulfate, filtered, and concentrated to give the titlecompound as an oil (4.90 g). ¹H NMR (d6-DMSO, 400 MHz) δ (ppm): 3.44 (t,J=5.6 Hz, 2H), 2.54 (t, J=6.0 Hz, 2H), 2.40 (d, J=5.6 Hz, 2H), 1.31-1.25(m, 5H), 0.83 (t, J=6.8 Hz, 6H).

b. (2-Ethylbutyl)-(2-hydroxyethyl)-carbamic acid tert-butyl ester

To the solution of the product of the previous step (3.0 g, 20.7 mmol)in DCM (30 mL) at 0° C. was added a solution of di-tert-butyldicarbonate (4.06 g, 18.6 mmol) dropwise over 5 min. The resultingmixture was warmed to room temperature and stirred overnight under anatmosphere of nitrogen. The crude reaction mixture was diluted with DCM(50 mL) and washed successively with 1 N aq HCl (2×50 mL), saturatedNaHCO₃ (2×50 mL) and brine 2×50 mL). The organic layer was dried overmagnesium sulfate, filtered, and concentrated to yield the titlecompound (5.4 g). ¹H NMR (d₆-DMSO, 400 MHz) δ (ppm): 4.62 (br s, 1H)3.44 (t, J=6.0 Hz, 2H), 3.2 (m, 2H), 3.09 (d, J=7.2 Hz, 2H), 1.50 (m,overlap with solvent, 1H), 1.38 (s, 9H), 1.25-1.87 (m, 4H), 0.83 (t,J=7.2 Hz, 6H).

c. (2-Ethylbutyl)-(2-oxoethyl)carbamic acid tert-butyl ester

To a solution of the product of the previous step (3.4 g, 13.9 mmol) inDCM (20 mL) at 0° C. was added sequentially DMSO (1.63 g, 20.9 mmol),DIPEA (4.48 g, 34.7 mmol) and sulfur trioxide pyridium complex (5.5 g,34.7 mmol). The reaction mixture was stirred for 16 h, diluted with DCM(20 mL) and washed successively with 1N aqueous HCl (50 mL), saturatedNaHCO₃ (50 mL) and brine (50 mL). The organic layer was dried overmagnesium sulfate, filtered, and concentrated. The crude material wasfiltered through silica gel and eluted with DCM. After concentration,the title compound was obtained as a dark orange oil (2.34 g). (m/z):[M+H]⁺ calcd for C₁₃H₂₅NO₃, 244.18. found, 244.0.

d.2-[3-endo-(3-Carbamoyl-2-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl-(2-ethylbutyl)-carbamicacid tert-butyl ester

To a flask were added3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide TFA salt (0.260g, 0.722 mmol), (2-ethylbutyl)-(2-oxoethyl)carbamic acid tert-butylester (0.211 g, 0.866 mmol), and DIPEA (126 μL, 0.72 mmol) in DCM (8.7mL) followed by sodium triacetoxyborohydride (0.184 g, 0.866 mmol). Thereaction mixture was concentrated and purified by preparative HPLC toprovide the title compound as its TFA salt (0.360 g). (m/z): [M+H]⁺calcd for C₂₇H₄₃N₃O₄, 474.33. found 474.4.

e.3-endo-(8-[2-(2-Ethylbutylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl-2-hydroxybenzamide

The product of the previous step (0.360 g, 0.760 mmol) was dissolved inDCM (10 mL). Trifluoroacetic acid (10 mL) was added and the reactionmixture was stirred for 2 h, concentrated, and dissolved in water (5 mL)and acetonitrile (5 g). The resulting solution was frozen andlyophilized to give the title compound (220 mg) which was used withoutfurther purification. (m/z): [M+H]⁺ calcd for C₂₂H₃₅N₃O₂, 374.27. found373.8.

Preparation 9:3-endo-(8-2-[(4,4-Difluorocyclohexylmethyl)amino]-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamidea. (4,4-Difluorocyclohexyl)methanol

To a reaction mixture of 4,4-difluorocyclohexanecarboxylic acid ethylester (7.1 g, 37 mmol) in THF (50 mL) cooled to 0° C. was added dropwise2.0 M lithium tetrahydroaluminate in THF (18.5 mL) over 10 min. Thereaction mixture was stirred at 0° C. for 1 h. Water (5 mL) was addeddropwise, followed by 1.0N NaOH (5 mL). The reaction mixture wasfiltered through Celite, THF was evaporated, and the resulting aqueoussolution was diluted with brine (50 mL) and extracted with ethyl acetate(50 mL). The organic layer was collected, dried over anhydrous sodiumsulfate, filtered, and concentrated to give the title compound as aclear oil (5.6 g) which was used without further purification.

b. Methanesulfonic acid 4,4-difluorocyclohexylmethyl ester

To the product of the previous step (5.5 g, 0.037 mol) andtriethylenediamine (4.11 g, 0.0366 mol) in DCM (50 mL) cooled to 0° C.was added dropwise methanesulfonyl chloride (3.12 mL, 0.0403 mol). Thereaction mixture was stirred at 0° C. for 30 min, warmed to roomtemperature, and washed with water (100 mL). The organic layer wascollected, dried over anhydrous sodium sulfate, filtered, andconcentrated to give the title compound as a white solid (8.5 g) whichwas used without further purification.

c. 2-[(4,4-Difluorocyclohexylmethyl)amino]ethanol

A solution of the product of the previous step (8.4 g, 0.037 mol) andethanolamine (20 mL, 0.4 mol) in ethanol (20 mL) was stirred at 65° C.overnight. The reaction mixture was concentrated, and extracted withethyl acetate (50 mL) and water (150 mL). The organic layer was washedwith water (100 mL) and then with brine (50 mL). The organic layer wascollected, dried over anhydrous sodium sulfate, filtered, andconcentrated to give the title compound (3.3 g).

d. (4,4-Difluorocyclohexylmethyl)-(2-hydroxyethyl)carbamic acidtert-butyl ester

To a solution of the product of the previous step (3.0 g, 16 mmol) andDIPEA (2.70 mL) in DCM (80 mL) was added dropwisedi-tert-butyldicarbonate (2.7 g, 12 mmol) in DCM (20 mL). The reactionmixture was stirred for 1 h, washed with 0.1N HCl (150 mL), and thenwashed with water (100 mL) The organic layer was collected, dried overanhydrous sodium sulfate, filtered, and concentrated to give the titlecompound as a yellow oil (4.0 g).

e. (4,4-Di fluorocyclohexylmethyl)-(2-oxoethyl)-carbamic acid tert-butylester

To a solution of DIPEA (4.75 mL) and the product of the previous step(4.0 g, 0.0136 mol) in DCM (20 mL) cooled to −20° C. was added sulfurtrioxide-pyridine complex (4.34 g, 0.0273 mol) in DMSO (20 g). Thereaction mixture was stirred for 1 h and then DCM (50 mL) was added. Thereaction mixture was washed with 10% AcOH in water (100 mL) and withwater (100 mL). The organic layer was collected, dried over anhydroussodium sulfate, filtered, and concentrated to give an oil. The crudeproduct was purified by flash column chromatography eluting with 10 to40% ethyl acetate in hexanes to give the title compound as an oil (2.8g).

f.3-endo-(8-2-[(4,4-Difluorocyclohexylmethyl)amino]-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide

To a solution of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamideTFA salt (0.10 g, 0.278 mmol) (Preparation 6), the product of theprevious step (0.130 g, 0.447 mmol) and DIPEA (70.7 μL, 0.406 mmol) inDCM (5 mL) was added sodium triacetoxyborohydride (0.0946 g, 0.447 mmol)The reaction mixture was stirred for 1 h and then concentrated. DCM (5mL) was added followed by trifluoroacetic acid (5 mL, 0.06 mol). Thereaction mixture was stirred for 30 min, concentrated and purified bypreparative HPLC to give the title compound as its TFA salt (0.102 g).(m/z): [M+H]⁺ calcd for C₂₃H₃₃F₂N₃O₂, 422.25. found 422.0.

Preparation 10:3-endo-(8-[2-(2,2-Dimethylpropylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamidea. 2,2-Dimethylpropyl-(2-oxoethyl)-carbamic acid benzyl ester

To a solution of pivaldehyde (1.00 mL, 0.00921 mol) in DCM (30 mL) wasadded 2,2-diethoxy-ethanamine, (1.35 mL, 0.00921 mol) followed by sodiumtriacetoxyborohydride (2.15 g, 0.0101 mol). The reaction mixture wasstirred at room temperature for 1 h and then DIPEA (1.43 g, 0.0110) mol)was added. The reaction mixture was cooled to 0° C., and benzylchloroformate (1.88 g, 0.0110 mol) was added dropwise. The reactionmixture was stirred for 1 h, concentrated, and 6 M TFA in water (20 mL)was added. The reaction mixture was stirred for 2 h and the TFA wasremoved under vacuum. The resulting aqueous solution was diluted withsaturated NaCl (15 mL) The product was extracted with ethyl acetate (25mL. The organic layer was collected, dried over anhydrous sodiumsulfate, filtered, and concentrated. The crude product was purified byflash column chromatography eluting with 10-20% ethyl acetate in hexanesto give an oil (2.2 g) which was further purified by flash columnchromatography to give the title compound as a yellow oil (0.72 g).

b.2-[3-endo-(3-Carbamoyl-2-hydroxyphenyl)-8-azabicyclo[3.2.1]oct-8-yl]-ethyl-(2,2-dimethyl-propyl)carbamicacid benzyl ester

To a solution of 3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamideTFA salt (0.10 g, 0.278 mmol) (Preparation 6), the product of theprevious step (80.4 mg, 0.305 mmol) in DCM (5 mL, 0.08 mol) was addedDIPEA (48.3 μL, 0.27 mmol) followed by sodium triacetoxyborohydride(70.6 mg, 0.333 mmol). The reaction mixture was stirred for 1 h,concentrated, and purified by preparative HPLC to give the titlecompound as its TFA salt (0.15 g). (m/z): [M+H]⁺ calcd for C₂₉H₃₉N₃O₄,494.29. found 494.6.

c.3-endo-(8-[2-(2,2-Dimethylpropylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide

To a solution of the product of the previous step (0.150 g, 0.247 mmol)in methanol (5 mL, 0.1 mol) was added 10% Pd/C (0.1:0.9,palladium:carbon black, 15 mg). The reaction mixture was stirred underan atmosphere of hydrogen for 2 h, filtered through Celite, andconcentrated to give the title compound as a white solid (0.12 g).(m/z): [M+H]⁺ calcd for C₂₂H₃₅N₃O₂, 360.26. found 360.4.

Preparation 11: 3-endo-(8-Azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamidea. 3-Bromo-2-tert-butoxy-benzonitrile

A mixture of 3-bromo-2-fluoro-benzonitrile (40.0 g, 0.200 mol) andtetrahydrofuran (200 mL) was chilled to 0° C. and stirred for 5 min. Asolution of potassium tert-butoxide (130 mL, 0.210 mol) was addeddropwise at 0° C. and the reaction was allowed to warm to RT withstirring over 90 min. The reaction was quenched with water (200 mL) and2 M Na₂CO₃ (100 mL) and extracted with EtOAc (3×200 mL). The organiclayer was dried over Na₂SO₄ and the solvent was removed by rotaryevaporation to provide the title compound as a light yellow oil.

b.3-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-2-tert-butoxy-benzonitrile

To a solution of 3-bromo-2-tert-butoxy-benzonitrile (30.73 g, 0.121 mol)in THF (100 mL) at 0° C. was added 2 M isopropylmagnesium chloride inTHF (60 mL) dropwise. The reaction mixture was stirred for 1 h and thentetrakis(triphenylphosphine)palladium(0) (2.33 g, 0.002 mol) was addedfollowed by trifluoro-methanesulfonic acid8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl ester (35.00 g, 0.101 mol) inTHF (23 mL). The reaction mixture was refluxed at 80° C. for 1 h, cooledto RT, washed with brine, and extracted with EtOAc (2×). The organiclayer was dried over sodium sulfate and the solvent was evaporated toprovide the title compound (39.2 g) which was used without furtherpurification. (m/z): [M+H]⁺ calcd for C₂₅H₂₈N₂O 373.22. found 373.2.

c. 3-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-2-hydroxy-benzamide

Trifluoroacetic Acid (50 mL) and sulfuric acid (20 mL) were added tocrude3-(8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-2-tert-butoxy-benzonitrile(37.53 g, 0.101 mol) and the reaction mixture was heated at 65° C.overnight, poured into ice water and neutralized to pH 7. The aqueouslayer was extracted EtOAc (3×) and the solvent was evaporated. Thereaction mixture was purified by silica gel chromatography (10 min 7%MeOH:DCM, 10 min 10% MeOH: DCM, ramping to 20% MeOH:DCM over 30 min) toprovide the title compound (22.15 g). (m/z): [M+H]⁺ calcd for C₂₁H₂₂N₂O₂335.17. found 335.4

d. 3-endo-(8-Azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide

Ethanol (1.23 L) was slowly added to palladium (6.15 g, 0.058 mol) (10%Pd, 50% water). The reaction mixture was stirred for 5 min,3-(8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-2-hydroxy-benzamide (6.15g, 0.018 mol) in EtOH (40 mL) was added, and then ammonium formate(12.30 g, 0.195 mol) was added slowly. The reaction mixture was heatedat 60° C. for about 3 h and filtered through celite, washing with EtOH.The solvent was removed by rotary evaporation to provide the formic acidsalt of the title compound (5.46 g). (m/z): [M+H]⁺ calcd for C₁₄H₁₈N₂O₂247.14. found 247.4. ¹H NMR (DMSO-d₆, 600 MHz) δ (ppm): 8.54 (s, 1H),8.45 (s, 1H), 7.96 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.48 (d, J=7.32 Hz,1H), 6.82 (t, J=7.64 Hz, 1H), 3.92 (s, 2H), 3.35 (m, 2H), 2.37 (m, 2H),1.95 (m, 2H), 1.80 (m, 4H). Two-dimensional Nuclear Overhauser EffectSpectroscopy (NOESY) data was analyzed and found to be consistent withendo configuration.

Preparation 12:3-endo-(8-2-[(4,4-Difluoro-cyclohexylmethyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamidea. (4,4-Difluoro-cyclohexylmethyl)-(2-hydroxy-ethyl)-carbamic acidbenzyl ester

Benzyl chloroformate (4.8 mL, 33.2 mmol) was added to a solution of2-[(4,4-difluoro-cyclohexylmethyl)-amino]-ethanol (6.41 g, 33.2 mmol)and DIPEA (5.8 mL) in DCM (200 mL) and the reaction mixture was stirredfor 1 h. The reaction mixture was washed with 0.1 N HCl (150 mL) andthen with water (100 mL). The organic layer was collected, dried overanhydrous sodium sulfate, filtered, and concentrated to give the titleproduct as a clear oil (9.1 g) which partially crystallized overnight.

b. (4,4-Difluoro-cyclohexylmethyl)-(2-oxo-ethyl)-carbamic acid benzylester

A solution of DIPEA (9.68 mL, 0.056 mol) and the product of the previousstep (9.1 g, 0.028 mol) in DCM (40 mL) was cooled at −20° C. and sulfurtrioxide-pyridine complex (8.85 g, 0.056 mol) in dimethylsulfoxide (20mL) was added. The reaction mixture was stirred for 1 h and DCM (50 mL)was added. The reaction mixture was washed with 10% AcOH in water (100mL) and then with water (100 mL). The organic layer was collected, driedover anhydrous sodium sulfate, filtered, and concentrated to give anoil. The crude product was purified by silica gel chromatography elutingwith 10-40% ethyl acetate in hexanes to give the title compound as anoil (6.3 g).

c.2-[(3-endo-(3-Carbamoyl-2-hydroxy-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl-(4,4-difluoro-cyclohexylmethyl)-carbamicacid benzyl ester

Sodium triacetoxyborohydride (142 mg, 0.67 mmol) was added to a solutionof 3-endo-8-aza-bicyclo[3.2.1]oct-3-yl-2-hydroxy-benzamide TFA salt (220mg, 0.61 mmol), (4,4-difluoro-cyclohexylmethyl)-(2-oxo-ethyl)-carbamicacid benzyl ester (218 mg, 0.67 mmol), and DIPEA (110 μL, 0.61 mmol) inDCM (10 mL). The reaction mixture was stirred for 1 h, concentrated, andwas purified by preparative HPLC to give the TFA salt (0.260 g). Thecrude product was dissolved with DCM (10 mL) and washed with 1 M NaHCO₃(10 mL). The organic layer was collected, dried over anhydrous sodiumsulfate, filtered, and concentrated to give the title compound (215 mg).(m/z): [M+H]⁺ calcd for C₃₁H₃₉F₂N₃O₄, 556.29. found 556.2.

d.3-endo-(8-2-[(4,4-Difluoro-cyclohexylmethyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamide

The product of the previous step (215 mg, 0.39 mol) in methanol (10 mL)was added to palladium hydroxide (20 mg, 0.14 mmol). The reaction wasstirred under an atmosphere of hydrogen overnight. The reaction wasfiltered through celite and concentrated to give the title compound (160mg). (m/z): [M+H]⁺ calcd for C₂₃H₃₃F₂N₃O₂, 422.25. found 422.2.

Preparation 13:3-endo-[8-(3-Amino-propyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-hydroxy-benzamidea.3-endo-[3-(3-Carbamoyl-2-hydroxy-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-propyl-carbamicacid benzyl ester

Sodium triacetoxyborohydride (249 mg, 1.17 mmol) was added to a mixtureof 3-endo-8-aza-bicyclo[3.2.1]oct-3-yl-2-hydroxy-benzamide formic acidsalt (286 mg, 0.98 mmol) and (3-oxo-propyl)-carbamic acid benzyl ester(223 mg, 1.08 mmol) in DMF (3 mL). The reaction mixture was stirred for1 h, concentrated, and purified by preparative HPLC to give the titlecompound as its TFA salt (460 mg). (m/z): [M+H]⁺ calcd for C₂₅H₃₁N₃O₄438.23. found 438.2.

b.3-endo-[8-(3-Amino-propyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-hydroxy-benzamide

To a solution of the product of the previous step (460 mg, 0.83 mmol) inmethanol (10 mL) was added Pearlman's Catalyst, wet (0.1:0.4:0.5,palladium hydroxide:carbon black:water, 46 mg, 0.03 mmol). The reactionmixture was placed under an atmosphere of hydrogen and stirredovernight, filtered through celite, and concentrated to give the titlecompound as its TFA salt (310 mg). (m/z): [M+H]⁺ calcd for C₁₇H₂₅N₃O₂304.19. found 304.2.

Preparation 14:3-endo-8-[2-(Cyclohexylmethyl-amino)-ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl-2-hydroxy-benzamide

Sodium triacetoxyborohydride (453 mg, 2.14 mmol) was added to a mixtureof cyclohexylmethyl-(2-oxo-ethyl)-carbamic acid benzyl ester (309 mg,1.06 mmol), 3-endo-8-aza-bicyclo[3.2.1]oct-3-yl-2-hydroxy-benzamideformate (250 mg, 0.86 mmol) and DMF (5 mL). The reaction mixture wasstirred for 2 h, and extracted with ethyl acetate (10 mL) and saturatedNaHCO₃ (10 mL). The organic layer was collected, dried over anhydroussodium sulfate, filtered, and concentrated. The resulting solid wasdissolved with methanol (10 mL), and placed under an atmosphere ofnitrogen. Pearlman's catalyst, wet (0.1:0.4:0.5, palladiumhydroxide:carbon black:water, 0.25 mg) was added and the reactionmixture was stirred under an atmosphere of hydrogen overnight, filteredthrough celite, and concentrated, to provide the title intermediatewhich was used without further purification (270 mg). (m/z): [M+H]⁺calcd for C₂₃H₃₅N₃O₂ 386.27. found 386.6.

Example 13-endo-(8-{2-[((S)-2,3-Dihydroxypropionyl)-(2-ethylbutyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide

To a solution of3-endo-(8-[2-(2-ethylbutylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl-2-hydroxybenzamideTFA (20 mg, 0.033 mmol) (Preparation 8), lithium(S)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (5.56 mg, 0.0366 mmol) andDIPEA (17 μL, 0.10 mmol) in DMF (0.3 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (13.9 mg, 0.0366 mmol). The reaction mixture wasstirred for 2 h and concentrated. Acetic acid (0.5 mL) and water (0.5mL) were added and the reaction mixture was stirred at 75° C. overnight,cooled to room temperature, and purified by preparative HPLC to give thetitle compound as its TFA salt (8.0 mg). (m/z): [M+H]⁺ calcd forC₂₅H₃₉N₃O₅ 462.29. found: 462.3. ¹H NMR (CD₃OD 400 MHz) 7.7 (dd, 1H),7.6 (d, 1H), 6.9 (t, 1H), 4.6 (t, 1H), 4.2 (m, 1H), 4.1-4.0 (m, 2H), 3.8(3,2H), 3.7-3.6 (m, 1H), 3.6-3.3 (m, 3H), 3.3-3.2 (m, 2H), 2.8-2.6 (m,2H), 2.4-2.2 (m, 4H), 2.2-2.0 (m, 2H), 1.7-1.6 (m, 1H), 1.5-1.3 (m, 4H),1.1-0.9 (m, 6H).

Example 23-endo-(8-2-[(2-Ethylbutyl)-(2-hydroxyacetyl)amino]-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide

To a solution of3-endo-(8-[2-(2-ethylbutylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl-2-hydroxybenzamideTFA (65 mg, 0.11 mmol) (Preparation 8) and DIPEA (22 μL, 0.13 mmol) inDCM (2 mL) was added acetoxyacetyl chloride (14 μL, 0.13 mmol). Thereaction mixture was stirred for 1 h and concentrated. Methanol (5 mL)was added followed by 6 N NaOH (200 μL). The reaction mixture wasstirred at room temperature for 1 h, concentrated, and purified bypreparative HPLC to give the title compound as its TFA salt (33 mg).(m/z): [M+H]⁺ calcd for C₂₄H₃₇N₃O₄ 432.28. found: 432.8.

Example 33-endo-(8-2-[(2-Ethylbutyl)-(2-methanesulfonylacetyl)amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide

To a solution of3-endo-(8-[2-(2-ethylbutylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl-2-hydroxybenzamideTFA (20 mg, 0.033 mmol) (Preparation 8), 1 methanesulfonyl-acetic acid(5.05 mg, 0.0366 mmol) and DIPEA (17 μL, 0.10 mmol) in DMF (10.3 mL) wasadded N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (15 mg, 0.040 mmol). The reaction mixture wasstirred for 2 h, concentrated, and purified by preparative HPLC to givethe title compound as its TFA salt (8.8 mg). (m/z): [M+H]⁺ calcd forC₂₅H₃₉N₃O₅S 494.26. found: 494.6.

Example 43-endo-(8-2-[(4,4-Difluorocyclohexylmethyl)-(2-hydroxyacetyl)-amino]ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide

To a solution of3-endo-(8-2-[(4,4-difluorocyclohexylmethyl)amino]ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamideTFA salt (15 mg, 0.028 mmol) (Preparation 9) and DIPEA (12 μL, 0.071mmol) in DCM (5 mL) was added acetoxyacetyl chloride (4.6 μL, 0.0439mmol). The reaction mixture was stirred for 1 h and concentrated.Methanol (2 mL) was added followed by 6 N NaOH (60 μL). The reactionmixture was stirred at room temperature for 1 h, concentrated, andpurified by preparative HPLC to give the title compound as its TFA salt(9.2 mg). (m/z): [M+H]⁺ calcd for C₂₅H₃₅F₂N₃O₄ 480.26. found: 480.2.

Example 53-endo-(8-2-[(2,2-Dimethylpropyl)-(2-hydroxyacetyl)amino]-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide

Following the procedure of Example 4 using3-endo-(8-[2-(2,2-dimethylpropylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamideTFA salt (Preparation 10) in place of3-endo-(8-2-[(4,4-difluoro-cyclohexylmethyl)amino]ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamideTFA salt, the title compound was prepared as its TFA salt. (m/z): [M+H]⁺calcd for C₂₃H₃₅N₃O₄ 418.26. found: 418.8.

Example 63-endo-(8-{2-[((S)-2,3-Dihydroxypropionyl)-(2,2-dimethylpropyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide

Following the procedure of Example 1 using3-endo-(8-[2-(2,2-dimethyl-propylamino)ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamideTFA (Preparation 10) in place of3-endo-(8-[2-(2-ethylbutylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl-2-hydroxybenzamideTFA, the title compound was prepared as its TFA salt. (m/z): [M+H]⁺calcd for C₂₄H₃₇N₃O₅ 448.27. found: 448.2.

Example 73-endo-(8-{2-[Cyclohexylmethyl-(2-hydroxyacetyl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamidea. Acetic acid [cyclohexylmethyl-(2-hydroxyethyl)carbamoyl]-methyl ester

To a solution of 2-(cyclohexylmethylamino)-ethanol (600 mg, 3.8 mmol) inDCM (6 mL) at 0° C. was added DIPEA (588 mg, 4.6 mmol) and thenacetoxyacetyl chloride (467 mg, 3.44 mmol) over 5 min. The resultingmixture was warmed to room temperature, stirred overnight under anatmosphere of nitrogen, diluted with DCM and washed successively with 1N aqueous HCl, saturated NaHCO₃, and brine. The organic layer was driedover magnesium sulfate, filtered, and concentrated to yield the titlecompound (914 mg). (m/z): [M+H]⁺ calcd for C₁₃H₂₃NO₄, 258.16. found,258.0.

b. Acetic acid [cyclohexylmethyl-(2-oxo-ethyl)-carbamoyl]-methyl ester

To a solution of the product of the previous step (916 g, 3.56 mmol) inDCM (10 mL) at 0° C. was added sequentially DMSO (417 mg, 5.34 mmol),DIPEA (1.12 g, 8.9 mmol) and sulfur trioxide pyridium complex (1.42 g,8.9 mmol). The reaction mixture was stirred for 72 h, diluted with DCMand washed successively with 1 N aqueous HCl and brine. The organiclayer was dried over magnesium sulfate, filtered, and concentrated. Thecrude material was purified by flash chromatography (20 to 100% EtOAc inhexanes) to afford the title intermediate. After concentration, thetitle compound was obtained as dark orange oil (260 mg) and used in thenext step without further purification.

c. Acetic acid({2-[3-endo-(3-carbamoyl-2-hydroxyphenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]ethyl}cyclohexylmethyl-carbamoyl)-methylester

To a suspension of3-endo-(8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide TFA salt (32 mg,0.09 mmol) in DCM (0.3 mL) was added acetic acid[cyclohexylmethyl-(2-oxo-ethyl)-carbamoyl]-methyl ester (34 mg, 0.13mmol) and DIPEA (23 mg, 0.18 mmol). The reaction mixture was stirred for30 min, and then sodium triacetoxy borohydride (28 mg, 0.13 mmol) wasadded and the mixture was stirred for 1 h. The reaction mixture wasdiluted with DCM (1 mL) and washed with saturated sodium bicarbonate (2mL). The organic layer was concentrated to give the title compound whichwas used in next step without further purification (m/z): [M+H]⁺ calcdfor C₂₇H₃₉N₃O₅, 486.29. found, 486.4.

d.3-endo-(8-{2-[Cyclohexylmethyl-(2-hydroxyacetyl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide

The oily residue from the previous step was dissolved in ethanol (0.3mL) and treated with LiOH.H₂O (10 mg, 0.5 mmol) in water (0.08 mL) for 2h. The solvent was concentrated and the residue was dissolved in 50%acetic acid in water (1.2 mL), filtered, and purified by preparativeHPLC to give the title compound as its TFA salt (22.7 mg). (m/z): [M+H]⁺calcd for C₂₅H₃₇N₃O₄, 444.28. found, 445.0.

Example 83-endo-(8-2-[(4,4-Difluoro-cyclohexylmethyl)-((S)-2,3-dihydroxy-1-oxo-propyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamide

To a solution of3-endo-(8-2-[(4,4-difluoro-cyclohexylmethyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamide(60.0 mg, 0.14 mmol) and Lithium(S)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (32 mg, 0.21 mmol) in DMF(2 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (65 mg, 0.17 mmol). The reaction mixture was stirredovernight and concentrated. The resulting solid was stirred in 1:1AcOH:water at 70° C. overnight and purified by preparative HPLC to givethe title compound as its TFA salt (65 mg) (m/z): [M+H]⁺ calcd forC₂₆H₃₇F₂N₃O₅ 510.27. found 510.6.

Example 93-endo-(8-2-[(4,4-Difluoro-cyclohexylmethyl)-(2-methanesulfonyl-acetyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamide

To a solution of3-endo-(8-2-[(4,4-difluoro-cyclohexylmethyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamide(310 mg, 0.74 mmol) in DMF (2.1 mL) was added DIPEA (154 μL, 0.88 mmol)followed by methanesulfonyl-acetic acid (112 mg, 0.81 mmol) and thenN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (336 mg, 0.88 mmol). The reaction mixture wasstirred overnight, concentrated, and purified by preparative HPLC togive the title compound as it TFA salt (199 mg). ¹H NMR (CD₃OD, 400 mHz)δ (ppm) 7.69 (dd, J=8.0 Hz, 1.5 Hz, 1H), 7.70-7.64 (m, 2H), 7.44-7.34(m, 3H), 7.32 (dd, J=7.5 Hz, 1.8 Hz, 1H), 6.84 (t, J=7.8 Hz, 1H),6.6-6.1 (m, 1H), 4.12 (dd, J=17.8 Hz, 8.4 Hz, 2H), 3.80-3.68 (m, 2H),3.18-3.06 (m, 1H), 2.46-2.30 (m, 2H), 2.29-2.14 (m, 2H), 2.03-1.93 (m,1H). (m/z): [M+H]⁺ calcd for C₂₆H₃₇F₂N₃O₅S 542.24. found 542.6.

Examples 10 and 11

Following the process of Example 9 using the appropriate8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamide derivative, the TFAsalts of the following compounds were prepared:

Example 10:3-endo-(8-2-[(2,2-dimethyl-propyl)-(2-methanesulfonyl-acetyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamide(m/z): [M+H]⁺ calcd for C₂₄H₃₇N₃O₅S 480.25. found 480.0.

Example 11:3-endo-(8-2-[cyclohexylmethyl-(2-methanesulfonyl-acetyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamide(m/z): [M+H]⁺ calcd for C₂₆H₃₉N₃O₅S 506.26. found 506.2

Example 123-endo-(8-2-[Cyclohexylmethyl-((S)-2,3-dihydroxy-1-oxo-propyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamide

Following the process of Example 8 using the appropriate8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamide derivative, the TFAsalt of the title compound was prepared. (m/z): [M+H]⁺ calcd forC₂₆H₃₉N₃O₅ 474.29. found 474.2.

Example 133-endo-[8-(3-Benzoylamino-propyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-hydroxy-benzamide

Benzoyl chloride (5.56 μL, 0.05 mmol) was added to a solution of3-endo-[8-(3-amino-propyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-hydroxy-benzamideTFA (20 mg; 0.05 mmol) and DIPEA (16.7 μL, 0.10 mmol) in acetonitrile(0.50 mL) and DCM (0.50 mL). The reaction mixture was stirred for 30min, concentrated, and purified by preparative HPLC to give the titlecompound as its TFA salt (16 mg). (m/z): [M+H]⁺ calcd for C₂₄H₂₉N₃O₃408.22. found 408.2.

Examples 14 to 18

Following the procedure of Example 13, using the appropriate acidchloride (Examples 14 to 16) or the procedure of Example 9 using3-endo-[8-(3-amino-propyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-hydroxy-benzamideTFA and the appropriate acid (Examples 17 and 18), the TFA salts of thecompounds of Table 1 were prepared.

TABLE 1

Ex Calc Found No. R³ Formula [M + H]⁺ [M + H]⁺ 14 3-chlorophenylC₂₄H₂₈ClN₃O₃ 442.18 442.2 15 3,5-difluorophenyl C₂₄H₂₇F₂N₃O₃ 444.20444.2 16 3,5-dichlorophenyl C₂₄H₂₇Cl₂N₃O₃ 476.14 476.2 17 3-fluorophenylC₂₄H₂₉N₃O₃ 426.21 426.2 18 3-chloro-2-fluorophenyl C₂₄H₂₇ClFN₃O₃ 460.17460.2

Example 19N-{2-[3-endo-(3-Carbamoyl-2-hydroxy-phenyl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-N-(2-ethyl-butyl)-succinamicacid

To succinic anhydride (32 mg, 0.32 mmol) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (120 mg, 0.32 mmol) followed by a solution of3-endo-8-[2-(2-ethyl-butylamino)-ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl-2-hydroxy-benzamide(58.9 mg, 0.16 mmol) and DIPEA (81 mg, 0.63 mmol) in DMF (0.5 mL). Theresulting mixture was stirred at room temperature for 1 h. The reactionmixture was concentrated, dissolved in 1:1 AcOH:H₂O (1.5 mL), filteredand purified by preparative HPLC to provide the title compound as itsTFA salt (43.8 mg). (m/z): [M+H]⁺ calcd for C₂₆H₃₉N₃O₅ 474.29. found474.2.

Examples 20 to 26

Following the general procedure of Example 19, the TFA salts of thecompounds of Table 2 were prepared:

TABLE 2

Ex Calc Found No. R¹ R³ Formula [M + H]⁺ [M + H]⁺ 20 1- —CH₂C(O)OHC₂₅H₃₇N₃O₅ 460.27 460.2 ethylpropyl 21 1- —CH₂C(O)O— C₃₂H₄₃N₃O₅ 550.32550.2 ethylpropyl benzyl 22 4,4-diF— —CH₂C(O)O— C₃₃H₄₁F₂N₃O₅ 598.30598.2 chexyl benzyl 23 4,4-diF— —CH₂C(O)OH C₂₆H₃₅F₂N₃O₅ 508.25 508.2chexyl 24 4,4-diF— —(CH₂)₂C(O)OH C₂₇H₃₇F₂N₃O₅ 522.27 522.2 chexyl 25t-butyl —CH₂C(O)O— C₃₁H₄₁N₃O₅ 536.30 536.2 benzyl 26 t-butyl —CH₂C(O)OHC₂₄H₃₅N₃O₅ 446.26 446.2

Assay 1: Radioligand Binding Assay on Human Mu, Human Delta and GuineaPig Kappa Opioid Receptors

a. Membrane Preparation

CHO-K1 (Chinese Hamster Ovary) cells stably transfected with human muopioid or with guinea pig kappa receptor cDNA were grown in mediumconsisting of Ham's-F12 media supplemented with 10% FBS, 100 units/mlpenicillin −100 μg/mL streptomycin and 800 μg/mL Geneticin in a 5% CO₂,humidified incubator @ 37° C. Receptor expression levels (B_(max) ˜2.0and ˜0.414 pmol/mg protein, respectively) were determined using[³H]-Diprenorphine (specific activity ˜50-55 Ci/mmol) in a membraneradioligand binding assay.

Cells were grown to 80-95% confluency (<25 subculture passages). Forcell line passaging, the cell monolayer was incubated for 5 minutes atroom temperature and harvested by mechanical agitation in 10 mL of PBSsupplemented with 5 mM EDTA. Following resuspension, cells weretransferred to 40 mL fresh growth media for centrifugation for 5 minutesat 1000 rpm and resuspended in fresh growth medium at the appropriatesplit ratio.

For membrane preparation, cells were harvested by gentle mechanicalagitation with 5 mM EDTA in PBS followed by centrifugation (2500 g for 5minutes). The pellets were resuspended in Assay Buffer (50 mM4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acidN-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) (HEPES)), pH7.4, and homogenized with a polytron disrupter on ice. The resultanthomogenates were centrifuged (1200 g for 5 minutes), the pelletsdiscarded and the supernatant centrifuged (40,000 g for 20 minutes). Thepellets were washed once by resuspension in Assay Buffer, followed by anadditional centrifugation (40,000 g for 20 minutes). The final pelletswere resuspended in Assay Buffer (equivalent 1 T-225 flask/1 mL assaybuffer). Protein concentration was determined using a Bio-Rad BradfordProtein Assay kit and membranes were stored in frozen aliquots at −80°C., until required.

Human delta opioid receptor (hDOP) membranes were purchased from PerkinElmer. The reported K_(d) and B_(max) for these membranes determined bysaturation analyses in a [³H]-Natrindole radioligand binding assays were0.14 nM (pK_(d)=9.85) and 2.2 pmol/mg protein, respectively. Proteinconcentration was determined using a Bio-Rad Bradford Protein Assay kit.Membranes were stored in frozen aliquots at −80° C., until required.

b. Radioligand Binding Assays

Radioligand binding assays were performed in an Axygen 1.1 mL deep well96-well polypropylene assay plate in a total assay volume of 200 μLcontaining the appropriate amount of membrane protein (˜3, ˜2 and ˜20 μgfor mu, delta and kappa, respectively) in Assay Buffer, supplementedwith 0.025% bovine serum albumin (BSA). Saturation binding studies fordetermination of K_(d) values of the radioligand were performed using[³H]-Diprenorphine at 8-12 different concentrations ranging from 0.001nM-5 nM. Displacement assays for determination of pKi values ofcompounds were performed with [³H]-Diprenorphine at 0.5, 1.2, and 0.7 nMfor mu, delta, and kappa, respectively, and eleven concentrations ofcompound ranging from 10 pM-100 μM.

Binding data were analyzed by nonlinear regression analysis with theGraphPad Prism Software package (GraphPad Software, Inc., San Diego,Calif.) using the 3-parameter model for one-site competition. The curveminimum was fixed to the value for nonspecific binding, as determined inthe presence of 10 μM naloxone. K_(i) values for test compounds werecalculated, in Prism, from the best fit IC₅₀ values, and the K_(d) valueof the radioligand, using the Cheng-Prusoff equation(K_(i)=IC₅₀/(1+([L]/K_(d))) where [L]=the concentration of[³H]-Diprenorphine. Results are expressed as the negative decadiclogarithm of the K_(i) values, pK_(i).

Test compounds having a higher pK_(i) value in these assays have ahigher binding affinity for the mu, delta, or kappa opioid receptor. Thecompounds of Examples 1-26 were tested in these assays. All of thecompounds had a pK_(i) value between about 8.4 and about 10.7 at thehuman mu opioid receptor. For example, the compounds of Examples 1, 2,and 6 had pK_(i) values of 10.0, 10.0, and 9.6, respectively. Compoundsof the invention also exhibited pK_(i) values between about 7.5 andabout 10.2 at the human delta and guinea pig kappa opioid receptors.

Assay 2: Agonist Mediated Activation of the Mu-Opioid Receptor in,Membranes Prepared from CHO-K1 Cells Expressing the Human mu-OpioidReceptor

In this assay, the potency and intrinsic activity values of testcompounds were determined by measuring the amount of bound [³⁵S]GTPγSpresent following receptor activation in membranes prepared from CHO-K1cells expressing the human mu opioid receptor.

a. Mu Opioid Receptor Membrane Preparation:

Human mu opioid receptor (hMOP) membranes were either prepared asdescribed above or were purchased from Perkin Elmer. The reported pK_(d)and B_(max) for the purchased membranes determined by saturationanalyses in a [³H]-Diprenorphine radioligand binding assays was 10.06and 2.4 pmol/mg protein, respectively. Protein concentration wasdetermined using a Bio-Rad Bradford Protein Assay kit. Membranes werestored in frozen aliquots at −80° C., until required.

b. Human mu [³⁵S]GTPγS Nucleotide Exchange Assay

Membranes were prepared as described above, and prior to the start ofthe assay, aliquots were diluted to a concentration of 200 μg/mL inAssay Buffer (50 mM HEPES, pH 7.4 at 25° C.), then homogenized for 10seconds using a Polytron homogenizer. Test compounds were received as 10mM stock solutions in DMSO, diluted to 400 μM into Assay Buffercontaining 0.1% BSA, and serial (1:5) dilutions then made to generateten concentrations of compound ranging from 40 pM-80 μM. GDP and[³⁵S]GTPγS were diluted to 40 μM and 0.4 nM, respectively, in AssayBuffer. The assay was performed in a total volume of 200 μL, containing10 μg of membrane protein, test compound ranging from 10 pM-20 μM), 10μM GDP, and 0.1 nM [³⁵S]GTPγS diluted in 10 mM MgCl₂, 25 mM NaCl, and0.0125% BSA (final assay concentrations). A DAMGO(Tyr-D-Ala-Gly-(methyl)Phe-Gly-ol) concentration-response curve (rangingfrom 12.8 pM-1 μM) was included on every plate.

Assay plates were prepared immediately prior to assay following theaddition of 50 μL, of the NaCl/MgCl₂/GDP solution, 50 μL of testcompound, and 50 μL of [³⁵S]GTPγS. The assay was initiated by theaddition of 50 μL of membrane protein and allowed to incubate for 30minutes at room temperature. The reaction was terminated by filtrationonto 96-well GF/B filter plates, pre-blocked with 0.3% polyethylenimine,using a Packard Filtermate harvester, and wash with ice-cold AssayBuffer (3×200 μl). Plates are dried overnight prior to determination ofcounts bound via liquid scintillation on a Packard Topcount instrument.Vehicle: DMSO not to exceed 1% final assay concentration.

The amount of bound [³⁵S]GTPγS is proportional to the degree ofactivation of the mu opioid receptors by the test compound. Theintrinsic activity (IA), expressed as a percentage, was determined asthe ratio of the amount of bound [³⁵S]GTPγS observed for activation bythe test compound to the amount observed for activation by DAMGO whichis presumed to be a full agonist (IA=100). The compounds of theinvention tested in this assay demonstrated intrinsic activities of lessthan about 10. For example, the compounds of Examples 1, 3, and 6 had IAvalues of −1, −4, and 9, respectively. Thus, the compounds of thepresent invention have been shown to act as antagonists at the human muopioid receptor.

Assay 3: Rat Model of In Vivo Efficacy

In this assay the efficacy of test compounds was evaluated in a model ofgastrointestinal transit, which evaluates peripheral activity. Thisstudy was approved by the Institutional Animal Care and Use Committee atTheravance, Inc. and conformed to the Guide for the Care and Use ofLaboratory Animals published by the National Academy of Sciences(©1996).

a. Rat Gastric Emptying Assay

Test compounds were evaluated in the rat gastric emptying assay todetermine their ability to reverse loperamide-induced delayed gastricemptying. Rats were fasted up overnight prior to administration of testcompounds or vehicle by intravenous, subcutaneous, intramuscular or oralroutes of administration at doses ranging from 0.001 to about 30milligrams/kilogram (mg/kg). The administration of test compound wasfollowed by subcutaneous administration of loperamide at a dose of 1mg/kg or vehicle. Five minutes post loperamide or vehicleadministration, a non-nutritive, non-absorbable charcoal meal wasadministered via oral gavage and animals were allowed free access towater for the sixty minute duration of the experiment. Animals were theneuthanized via carbon dioxide asphyxiation followed by thoracotomy andthe stomach was carefully excised. The stomach was ligated at the loweresophageal sphincter and the pyloric sphincter to prevent additionalemptying during tissue removal. Gastric weight was then determined afterremoval of the ligatures.

b. Data Analysis and Results

Data was analyzed using the GraphPad Prism Software package (GraphPadSoftware, Inc., San Diego, Calif.). Percent reversal curves wereconstructed by non-linear regression analysis using the sigmoidal doseresponse (variable slope) model and best-fit ID₅₀ values werecalculated. Curve minima and maxima were fixed to loperamide controlvalues (indicating 0% reversal) and vehicle controls (indicating 100%reversal), respectively. Results are expressed as ID₅₀, the doserequired for 50% reversal of the effects of loperamide, in milligramsper kilogram. The compounds of Examples 1, 4, and 6 administered orally,exhibited ID₅₀ values of 0.11 mg/kg, 0.014 mg/kg. and 0.42 mg/kg,respectively in the gastric emptying model.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto. Additionally, all publications, patents, andpatent documents cited hereinabove are incorporated by reference hereinin full, as though individually incorporated by reference.

1-18. (canceled)
 19. A method of treating a mammal having a medicalcondition ameliorated by treatment with a mu opioid receptor antagonist,the method comprising administering to the mammal a therapeuticallyeffective amount of a pharmaceutical composition comprising apharmaceutically-acceptable carrier and a compound of formula (I):

wherein: R⁷ is hydrogen or —CH₂—R¹; R¹ is C₄₋₁₀ alkyl, C₃₋₁₂cycloalkyl,or phenyl, wherein C₃₋₁₂cycloalkyl and phenyl are each optionallysubstituted with one or two halo; R² is selected from —C(O)R³,—C(O)NHR⁴, —C(O)OR⁵, —S(O)₂R⁶, and —C(O)R⁸; R³ is C₁₋₆ alkyl substitutedwith one or two substituents selected from —OR^(a), —S(O)₂R^(b), and—C(O)R^(c); R⁴ and R⁵ are each independently C₁₋₆ alkyl substituted withone or two substituents selected from —OR^(a) and —S(O)₂R^(b); R⁶ isC₁₋₃alkyl; R⁸ is phenyl, optionally substituted with one or two halo;R^(a) is hydrogen or C₁₋₃alkyl; R^(b) is C₁₋₃alkyl; R^(c) is selectedfrom hydrogen, C₁₋₃alkyl, and benzyl; and m is 1 or 2; provided thatwhen R⁷ is hydrogen, R² is —C(O)R⁸; or a pharmaceutically-acceptablesalt thereof.
 20. The method of claim 19 wherein the compound of formula(I) is a compound of formula (Ia):

wherein: R² is selected from —C(O)R³, —C(O)NHR⁴, —C(O)OR⁵, and —S(O)₂R⁶;and R³, R⁴, and R⁵ are each independently C₁₋₆ alkyl substituted withone or two substituents selected from —OR^(a) and —S(O)₂R^(b); or apharmaceutically-acceptable salt thereof.
 21. The method of claim 20wherein R¹ is C₄₋₆alkyl or C₃₋₆cycloalkyl, wherein C₃₋₆cycloalkyl isoptionally substituted with one or two fluoro.
 22. The method of claim20 wherein R¹ is 1-ethylpropyl, tert-butyl, cyclohexyl, or4,4-difluorocyclohexyl.
 23. The method of claim 20 wherein the compoundof formula (Ia) is a compound of formula (Ic):


24. The method of claim 23 wherein R³ is C₁₋₃alkyl substituted with oneor two —OH or with one —S(O)₂CH₃.
 25. The method of claim 19 wherein thecompound is selected from:3-endo-(8-{2-[((S)-2,3-dihydroxypropionyl)-(2-ethylbutyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(2-ethylbutyl)-(2-hydroxyacetyl)amino]-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(2-ethylbutyl)-(2-methanesulfonylacetyl)amino]ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(4,4-difluorocyclohexylmethyl)-(2-hydroxyacetyl)-amino]ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(2,2-dimethylpropyl)-(2-hydroxyacetyl)amino]-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-{2-[((S)-2,3-dihydroxypropionyl)-(2,2-dimethylpropyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-{2-[cyclohexylmethyl-(2-hydroxyacetyl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(4,4-difluorocyclohexylmethyl)-((S)-2,3-dihydroxy-1-oxo-propyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;and3-endo-(8-2-[(4,4-difluorocyclohexylmethyl)-(2-methanesulfonylacetyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;and pharmaceutically-acceptable salts thereof.
 26. The method of claim19 wherein the medical condition is opioid-induced bowel dysfunction orpost-operative ileus.
 27. The method of claim 25 wherein the medicalcondition is opioid-induced bowel dysfunction or post-operative ileus.28. A method of reducing or preventing a side effect associated with useof an opioid agent in a mammal, the method comprising administering tothe mammal an opioid agent and a compound of formula (I):

wherein: R⁷ is hydrogen or —CH₂—R¹; R¹ is C₄₋₁₀ alkyl, C₃₋₁₂cycloalkyl,or phenyl, wherein C₃₋₁₂cycloalkyl and phenyl are each optionallysubstituted with one or two halo; R² is selected from —C(O)R³,—C(O)NHR⁴, —C(O)OR⁵, —S(O)₂R⁶, and —C(O)R⁸; R³ is C₁₋₆ alkyl substitutedwith one or two substituents selected from —OR^(a), —S(O)₂R^(b), and—C(O)R^(c); R⁴ and R⁵ are each independently C₁₋₆ alkyl substituted withone or two substituents selected from —OR^(a) and —S(O)₂R^(b); R⁶ isC₁₋₃alkyl; R⁸ is phenyl, optionally substituted with one or two halo;R^(a) is hydrogen or C₁₋₃alkyl; R^(b) is C₁₋₃alkyl; R^(c) is selectedfrom hydrogen, C₁₋₃alkyl, and benzyl; and m is 1 or 2; provided thatwhen R⁷ is hydrogen, R² is —C(O)R⁸; or a pharmaceutically-acceptablesalt thereof.
 29. The method of claim 28 wherein the compound of formula(I) is a compound of formula (Ia):

wherein: R² is selected from —C(O)R³, —C(O)NHR⁴, —C(O)OR⁵, and —S(O)₂R⁶;and R³, R⁴, and R⁵ are each independently C₁₋₆ alkyl substituted withone or two substituents selected from —OR^(a) and —S(O)₂R^(b); or apharmaceutically-acceptable salt thereof.
 30. The method of claim 29wherein R¹ is 1-ethylpropyl, tert-butyl, cyclohexyl, or4,4-difluorocyclohexyl.
 31. The method of claim 29 wherein the compoundof formula (Ia) is a compound of formula (Ic):


32. The method of claim 31 wherein R³ is C₁₋₃alkyl substituted with oneor two —OH or with one —S(O)₂CH₃.
 33. The method of claim 28 wherein thecompound is selected from:3-endo-(8-{2-[((S)-2,3-dihydroxypropionyl)-(2-ethylbutyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(2-ethylbutyl)-(2-hydroxyacetyl)amino]-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(2-ethylbutyl)-(2-methanesulfonylacetyl)amino]ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(4,4-difluorocyclohexylmethyl)-(2-hydroxyacetyl)-amino]ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(2,2-dimethylpropyl)-(2-hydroxyacetyl)amino]-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-{2-[((S)-2,3-dihydroxypropionyl)-(2,2-dimethylpropyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-{2-[cyclohexylmethyl-(2-hydroxyacetyl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(4,4-difluorocyclohexylmethyl)-((S)-2,3-dihydroxy-1-oxo-propyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;and3-endo-(8-2-[(4,4-difluorocyclohexylmethyl)-(2-methanesulfonylacetyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;and pharmaceutically-acceptable salts thereof.
 34. A method of enhancingmotility of the gastrointestinal tract in a mammal, the methodcomprising administering to the mammal a pharmaceutical compositioncomprising a pharmaceutically-acceptable carrier and a compound offormula (I):

wherein: R⁷ is hydrogen or —CH₂—R¹; R¹ is C₄₋₁₀ alkyl, C₃₋₁₂cycloalkyl,or phenyl, wherein C₃₋₁₂cycloalkyl and phenyl are each optionallysubstituted with one or two halo; R² is selected from —C(O)R³,—C(O)NHR⁴, —C(O)OR⁵, —S(O)₂R⁶, and —C(O)R⁸; R³ is C₁₋₆ alkyl substitutedwith one or two substituents selected from —OR^(a), —S(O)₂R^(b), and—C(O)R^(c); R⁴ and R⁵ are each independently C₁₋₆ alkyl substituted withone or two substituents selected from —OR^(a) and —S(O)₂R^(b); R⁶ isC₁₋₃alkyl; R⁸ is phenyl, optionally substituted with one or two halo;R^(a) is hydrogen or C₁₋₃alkyl; R^(b) is C₁₋₃alkyl; R^(c) is selectedfrom hydrogen, C₁₋₃alkyl, and benzyl; and m is 1 or 2; provided thatwhen R⁷ is hydrogen, R² is —C(O)R⁸; or a pharmaceutically-acceptablesalt thereof.
 35. The method of claim 34 wherein the compound of formula(I) is a compound of formula (Ia):

wherein: R² is selected from —C(O)R³, —C(O)NHR⁴, —C(O)OR⁵, and —S(O)₂R⁶;and R³, R⁴, and R⁵ are each independently C₁₋₆ alkyl substituted withone or two substituents selected from —OR^(a) and —S(O)₂R^(b); or apharmaceutically-acceptable salt thereof.
 36. The method of claim 35wherein R¹ is 1-ethylpropyl, tert-butyl, cyclohexyl, or4,4-difluorocyclohexyl.
 37. The method of claim 35 wherein the compoundof formula (Ia) is a compound of formula (Ic):


38. The method of claim 37 wherein R³ is C₁₋₃alkyl substituted with oneor two —OH or with one —S(O)₂CH₃.
 39. The method of claim 34 wherein thecompound is selected from:3-endo-(8-{2-[((S)-2,3-dihydroxypropionyl)-(2-ethylbutyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(2-ethylbutyl)-(2-hydroxyacetyl)amino]-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(2-ethylbutyl)-(2-methanesulfonylacetyl)amino]ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(4,4-difluorocyclohexylmethyl)-(2-hydroxyacetyl)-amino]ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(2,2-dimethylpropyl)-(2-hydroxyacetyl)amino]-ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-{2-[((S)-2,3-dihydroxypropionyl)-(2,2-dimethylpropyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-{2-[cyclohexylmethyl-(2-hydroxyacetyl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;3-endo-(8-2-[(4,4-difluorocyclohexylmethyl)-((S)-2,3-dihydroxy-1-oxo-propyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;and3-endo-(8-2-[(4,4-difluorocyclohexylmethyl)-(2-methanesulfonylacetyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamide;and pharmaceutically-acceptable salts thereof.